Table 1. Case series of actionable variant reclassifications.
| Pts | Gene | Variant | Type | Sex | Age at End of Study | Self Reported Race | Maternal - Paternal Ancestry | Affected status (age at diagnosis) | Summary of Reclassifi-cation Events | Adult Living FDRs | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Total | Women | Men | ||||||||||
| Upgrades | ||||||||||||
| 1 | BRCA1 | p.Arg1495Lys | Missense | F | 41 | Other | Salvadorean - Salvadorean | BR (39) | VUS-->LP-->P | 5 | 3 | 2 |
| 2 | BRCA1 | p. Arg1495Met | Missense | F | D @ 51 | White | Italian - Italian | Ov (46) | VUS-->P | 2 | 1 | 1 |
| 3 | BRCA1 | p.Thr1691Lys | Missense | F | 59 | Asian | Chinese/Indonesian - Chinese/Indonesian | DCIS (47) | VUS--LP | 11 | 5 | 6 |
| 4 | BRCA1 | p.Gly1706Glu | Missense | F | 59 | White | Armenian - German | Br (31) Br (42) Br (51) |
VUS--LP | 4 | 3 | 1 |
| 5 | BRCA2 | p.Trp2626Cys | Missense | F | 45 | White | English/Scottish/Swedish - Norwegian | Br (40) | VUS-->LP | 4 | 1 | 3 |
| 6 | BRCA2 | p.Gly2793Arg | Missense | F | 75 | Other | Mexican - Mexican | Br (43) Br (60) |
VUS-->LP--P | 19 | 8 | 11 |
| 7 | BRCA2 | c.8754+4A>G | Splice site/intronic | F | D @ 53 | White | Italian - Italian | Br (37) Ov (52) |
VUS-->LP--P | 3 | 1 | 2 |
| 8 | BRCA2 | p.Arg3052Trp | Missense | F | 50 | Other | Mexican - Guatemalan/Mexican | Br (34) Br (45) |
VUS-->P | 3 | 2 | 1 |
| 9 | BRCA2 | p.Asp3095Glu | Missense | F | 46 | White | Unknown - Unknown | Br (37) | VUS-->P | 4 | 2 | 2 |
| 10 | BRIP1 | c.3196delT | Nonsense/frameshift | F | 42 | African American | African American - African American | Br (41) | VUS-->LP | 3 | 1 | 2 |
| 11 | MLH1 | p.Thr117Met | Missense | F | 58 | White | Irish - Irish | Br (39) CRC (40) UT (40) |
VUS-->P | 4 | 1 | 3 |
| 12 | MSH2 | p.Ser554Arg | Missense | F | 51 | American Indian/ Alaska Native |
Native American - Native American | Sebaceous skin neoplasia (39) | VUS-->LP | 6 | 2 | 4 |
| 13 | MSH2 | p.Asn596del | inframe indel | M | D @ 79 | White | Scottish/Irish - German | CRC (57) Pan (57) CRC (69) T Cell Lymphoma (74) |
VUS-->P | 3 | 3 | 0 |
| 14 | MSH2 | p.Asn596del | inframe indel | F | 59 | White | Scottish/Irish - German | SqCC (38) Ut (44) Colon polyps (40) |
VUS-->P | 3 | 2 | 1 |
| 15 | MSH2 | p.Ala636Pro | Missense | F | 69 | White | Russian - Russian | CRC (46) Ut (53) Sebaceous skin neolasia (64) Sarcoma (70) |
VUS-->LP | 5 | 2 | 3 |
| 16 | SDHB | p.Ile127Ser | Missense | M | 57 | White | Irish/Scottish - Irish/Scottish | Paraganglioma (25) Pheochromocytoma (26) |
VUS-->P | 6 | 4 | 2 |
| Downgrades | ||||||||||||
| 1 | BRCA1 | c.4096+1G>A | Splice site/intronic | F | 68 | Other | Syrian - English | Br (46) | VUS-->LP-->P-->VUS | 7 | 6 | 1 |
| 2 | BRCA1 | c.4096+1G>A | Splice site/intronic | F | 64 | Other | Syrian - English | Br (45) | LP-->P-->VUS | 6 | 4 | 2 |
| 3 | BRCA1 | c.4096+1G>A | Splice site/intronic | F | 41 | Other | Syrian - English | Unaffected | LP-->P-->VUS | 4 | 3 | 1 |
| 4 | MET | c.1200+2T>C | Splice site/intronic | F | 71 | White | Irish/Scandinavian/Spanish - European | Br (68) Colon Polyps (68) |
LP-->VUS | 9 | 4 | 5 |
| 5 | MLH1 | dup exons 16-19 | Exonal duplication(s) | F | 54 | White | Armenian/Syrian - Armenian | Unaffected | LP*-->VUS | 8 | 7 | 1 |
| 6 | MSH2 | p.Met1Leu | Missense | F | 63 | White | Unknown - Unknown (West European) | Unaffected | LP-->P-->VUS | 6 | 4 | 2 |
| 7 | MSH2 | dup exons 1-4 | Exonal duplication(s) | F | 81 | Asian | Taiwanese - Taiwanese | CRC (66) Ut (71) Lung (76) |
LP-->VUS | 11 | 6 | 5 |
| 8 | NBN | p.Arg215Trp | Missense | F | 48 | Other | Mexican - Mexican | Br (45) | P-->VUS | 11 | 5 | 6 |
| 9 | PTEN | p.Ala79Thr | Missense | F | 55 | White | Italian - Croatian/Serbian | Unaffected | P-->VUS | 3 | 1 | 2 |
| Total relatives | 150 | 81 | 69 | |||||||||
Abbreviations: Participants (pts); deceased (D); breast (Br), colorectal cancer (CRC), uterine (Ut), ovarian (Ov), ductal carcinoma in situ (DCIS), pancreatic (Pan), squamous cell cancer of the skin (SqCC); reclassifications: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS); first-degree relative (FDR). It should be noted that some individuals had multiple rounds of reclassification, one that started and ended in the VUS category.