Submissions for variant NM_000059.4(BRCA2):c.9509A>G (p.Asp3170Gly)

gnomAD frequency: 0.00001  dbSNP: rs80359224

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000114127	SCV000244494	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-08-10	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 = 0.0000264
Ambry Genetics	RCV000163018	SCV000213506	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV001573223	SCV000522107	likely benign	not provided	2019-02-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24323938, 21990134, 17924331, 18951446, 19043619, 18951436, 29394989, 29988080, 29884841)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000440286	SCV000600865	benign	not specified	2021-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000440286	SCV000602759	benign	not specified	2016-08-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163018	SCV000689205	likely benign	Hereditary cancer-predisposing syndrome	2017-09-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000440286	SCV000695249	benign	not specified	2021-09-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9509A>G (p.Asp3170Gly) results in a non-conservative amino acid change located in the OB3 fold (IPR015188) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 3/60466 cases, but was also found in 4/53461 controls (Dorling_2021 through LOVD). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated similar homology-directed DNA damage repair (HDR) activity to the wild-type (Mesman_2018, Guidugli_2018). Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). Karchin_2008 classified variant as neutral based on protein likelihood ratio classification. Seven other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (n=4) / benign (n=3; including the expert panel). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770737	SCV000902220	likely benign	Breast and/or ovarian cancer	2021-11-29	criteria provided, single submitter	clinical testing
Invitae	RCV001394429	SCV001596113	likely benign	Hereditary breast ovarian cancer syndrome	2023-10-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163018	SCV002532043	likely benign	Hereditary cancer-predisposing syndrome	2022-01-19	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001573223	SCV002545118	likely benign	not provided	2022-06-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4, BS3:Supporting
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001394429	SCV002819190	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-09-12	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000440286	SCV004242584	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894888	SCV004709916	likely benign	BRCA2-related condition	2023-11-06	criteria provided, single submitter	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114127	SCV000147660	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354287	SCV001548866	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp3170Gly variant was identified in the literature however the frequency of this variant in an affected population was not provided (Easton 2007, Karchin 2008, Guidugli 2018, Lindor 2012). The variant was also identified in dbSNP (ID: rs80359224) as "With other allele", in ClinVar (classified as benign by Ambry Genetics, ENIGMA, Quest Diagnostics, and ARUP Laboratories; as likely benign by Gene Dx, Color; and as uncertain significance by BIC and Integrated Genetics), LOVD 3.0 (7 entries), and UMD-LSDB (2 entries). The variant was identified in control databases in 1 of 246074 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 111560 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Several variant model prediction programs conclude that the p.Asp3170Gly variant is not pathogenic (Easton 2007, Karchin 2008, Lindor 2012). A homology-directed DNA repair (HDR) assay in V-C8 cultured cells concluded that this variant was comparable to wild type and was classified as neutral (Guidugli 2018). The Asp3170 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573223	SCV001798761	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000440286	SCV001971569	benign	not specified		no assertion criteria provided	clinical testing