Submissions for variant NM_000059.4(BRCA2):c.8117A>G (p.Asn2706Ser)

gnomAD frequency: 0.00001  dbSNP: rs80359055

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001086095	SCV000073438	benign	Hereditary breast ovarian cancer syndrome	2024-01-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164845	SCV000215528	likely benign	Hereditary cancer-predisposing syndrome	2019-01-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000424555	SCV000520978	likely benign	not specified	2017-10-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588306	SCV000600786	likely benign	not provided	2021-07-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000424555	SCV000695129	likely benign	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8117A>G (p.Asn2706Ser) results in a conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 251544 control chromosomes, predominantly at a frequency of 0.00052 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.8117A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality (Saxena_2002, Yassaee_2002, Azzollini_2016, Shah_2018, Dorling_2021). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 6/60466 cases and 4/53461 controls (Dorling_2021 through LOVD). These data do not allow any conclusion about variant significance. At-least two co-occurrences with other pathogenic variant(s) have been reported (BRCA1 4476+2T>C from Saxena_2002; unspecified pathogenic mutation from Azzollini_2016), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 19043619, 12442273, 29785135, 12100744, 33471991). ClinVar contains an entry for this variant (Variation ID: 38139). Based on the evidence outlined above, the variant was classified as likely benign.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000031721	SCV000746283	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000031721	SCV000785637	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164845	SCV000902913	benign	Hereditary cancer-predisposing syndrome	2017-03-27	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798053	SCV002043513	uncertain significance	Breast and/or ovarian cancer	2020-05-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000164845	SCV002531910	likely benign	Hereditary cancer-predisposing syndrome	2020-10-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000424555	SCV002551757	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588306	SCV004033247	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS2
Sharing Clinical Reports Project (SCRP)	RCV000031721	SCV000054328	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031721	SCV000147276	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Integrative Tumor Epidemiology Branch, National Institutes of Health	RCV002266909	SCV002549698	uncertain significance	Chordoma	2021-03-22	no assertion criteria provided	research	No impact on ES cell survival or drug sensitivity (no impact on BRCA2 function)
BRCAlab, Lund University	RCV000031721	SCV004243801	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing