Submissions for variant NM_000059.4(BRCA2):c.2698A>G (p.Asn900Asp)

gnomAD frequency: 0.00001  dbSNP: rs55736268

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113078	SCV001161610	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000293
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044039	SCV000072052	likely benign	Hereditary breast ovarian cancer syndrome	2025-02-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130836	SCV000185734	likely benign	Hereditary cancer-predisposing syndrome	2019-03-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Counsyl	RCV000113078	SCV000488497	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000587512	SCV000567000	likely benign	not provided	2020-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18284688, 23929434, 20167696, 28843361, 26580448, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824589	SCV000694619	benign	not specified	2022-01-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.2698A>G (p.Asn900Asp) results in a conservative amino acid change in 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 4.1e-05 in 242556 control chromosomes, predominantly at a frequency of 6.3e-05 within the Non-Finnish European subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2698A>G, has been reported in the literature in an individuals affected with breast cancer and other tumor phenotypes (examples: Lee_2008 and Zhang_2015), but was also found in healthy controls (Dorling_2021 through LOVD). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.68_69delAG (p.Glu23ValfsX17), and BRCA1 c.2722G>T (p.Glu908X); in two internal samples), providing supporting evidence for a benign role. Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=3), likely benign (n=4), while the expert panel classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000130836	SCV000903070	likely benign	Hereditary cancer-predisposing syndrome	2016-02-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001824589	SCV001469669	likely benign	not specified	2023-10-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113078	SCV004845047	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service	RCV005237467	SCV005882939	benign	Inherited breast cancer and ovarian cancer	2024-10-01	criteria provided, single submitter	clinical testing	BP1,BP4,BP5_Strong
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113078	SCV000146090	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000044039	SCV001977049	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-09-27	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732606	SCV005346866	likely benign	BRCA2-related disorder	2024-04-01	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).