Table 2.

Comparison of medical management recommendations for discrepant variants

	Classification		Fisher’s exact P-value
	P/LP	VUS
	N (%)	N (%)
CDKN2A c.146T>Ca
Skin exam recommended
No	0 (0%)	9 (81.8%)	0.077c
Yes	2 (100%)	2 (18.2%)b
Total	2	11
Pancreatic cancer screening recommended
No	1 (50.0%)d	11 (100%)	0.154f
Yes	1 (50.0%)e	0 (0%)
Total	2	11
Targeted variant testing recommended
No	1 (50.0%)g	10 (90.9%)	0.295
Yes	1 (50.0%)	1 (9.1%)h
Total	2	11
CHEK2 c.470T>C
Colonoscopy frequencyi
General population or no recommendation given	2 (22.2%)	3 (60.0%)	0.266
Every 5 years or more frequently	7 (77.8%)	2 (40.0%)j
Total	9	5
Breast MRI recommendedk
No	2 (25.0%)	2 (50.0%)	0.547
Yes	6 (75.0%)	2 (50.0%)l
Total	8	4
Targeted variant testing recommendedm
No	1 (20.0%)n	5 (83.3%)	0.08
Yes	4 (80.0%)	1 (16.7%)o
Total	5	6
MUTYH c.934–2A>G
Colonoscopy frequencyp
General population or no recommendation given	1 (6.7%)	2 (100%)	0.022*
Every 5 years or more frequently	14 (93.3%)	0 (0%)
Total	15	2
Targeted variant testing or MUTYH sequencing recommended
No	2 (15.4%)	2 (100%)	0.057
Yes	11 (84.6%)	0 (0%)
Total	13	2

P/LP represents a classification of pathogenic/likely pathogenic. Cancer screening recommendations are for individual patients, and targeted variant testing refers to testing of family members for the respective variant. MUTYH sequencing refers to sequencing of the gene to assess either for the presence of biallelic P/LP variants, which would result in MUTYH associated polyposis syndrome (MAP), or to assess status of the patient’s partner to ascertain risk of MAP in offspring. Total N for familial testing represents total unique families.

^aDocumentation of results disclosure was unavailable for three individuals with VUS classifications.

^bOne had a personal history of melanoma, and one had a family history of melanoma.

^cWhen controlling for no personal or family history of melanoma, Fisher’s exact P = 0.018*.

^dPatient already affected with this disease. Knowledge of conflicting interpretations was not apparent.

^eNo personal or family history of pancreatic cancer. Results disclosure note discussed other laboratories’ VUS classification, indicating that provider was aware of conflict. Patient was under recommended age to begin screening, and note discussed the possibility for recommendations to change due to the ambiguity of the variant. Patient recommended to return to clinic in two years for updated management recommendations.

^fWhen controlling for no personal or family history of pancreatic cancer, Fisher’s exact P = 0.083.

^gProvider displayed awareness of conflict, and this appeared to play a role in not recommending familial testing.

^hVUS tracking studies recommended for family history of melanoma.

ⁱOne deceased patient, one with incomplete data, and three with active metastatic disease were excluded, as cancer screening recommendations were not provided or available.

^jBoth demonstrated provider awareness of conflicting interpretations; no family history of colorectal cancer.

^kOnly females were included.

^lOne also had a pathogenic variant in ATM that appeared to drive this recommendation; the other had demonstrated provider awareness of conflicting interpretations.

^mThere were 13 unique families with this variant; one was excluded because the patient was deceased when the results were received, and no recommendations were provided, and the other was excluded because all at-risk family members had already been tested for the variant prior to presenting to Cancer Genetics.

ⁿUnclear why not recommended; not discussed in clinic note. It may be possible that it was recommended but not documented in the note.

^oAppeared to be driven by knowledge of conflict.

^pDocumentation of results disclosure was available for 18 patients. One patient was added because although there was no CRF or original genetics results disclosure note, there was another provider’s note available which discussed the colonoscopy recommendations from the genetics provider. One deceased patient and one with incomplete data were excluded.