Submissions for variant NM_000059.4(BRCA2):c.7994A>G (p.Asp2665Gly)

gnomAD frequency: 0.00048  dbSNP: rs28897745

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000031716	SCV001161618	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 = 2.60E-07
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045378	SCV000073391	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129068	SCV000183769	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: 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.
GeneDx	RCV000590485	SCV000210663	likely benign	not provided	2021-02-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17924331, 20104584, 27741520, 28050887, 28758972, 21120943, 18724707, 21952622, 21702907, 21520273, 22505045, 16489001, 19043619, 21990134, 23108138, 20215541, 12474142, 24916970, 28324225, 18559594, 16826315, 20127978, 16758124, 25682074, 24323938, 29394989, 31131967, 32772980, 32438681, 29884841)
Counsyl	RCV000031716	SCV000220998	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-12-30	criteria provided, single submitter	literature only
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768637	SCV000324847	likely benign	Breast and/or ovarian cancer	2023-06-16	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000160248	SCV000538503	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 7 reports in HGMD, 3 describe as neutral/nonpathogenic; ClinVar: 5 labs report as B/LB
Color Diagnostics, LLC DBA Color Health	RCV000129068	SCV000683933	likely benign	Hereditary cancer-predisposing syndrome	2014-11-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590485	SCV000695116	benign	not provided	2016-01-29	criteria provided, single submitter	clinical testing
Mendelics	RCV000045378	SCV000838864	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112746	SCV001270437	uncertain significance	Fanconi anemia complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000031716	SCV001270438	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000160248	SCV002067027	likely benign	not specified	2017-09-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129068	SCV002531900	benign	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160248	SCV002551735	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590485	SCV003800094	likely benign	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031716	SCV000054323	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031716	SCV000147244	benign	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	RCV001353857	SCV000592168	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Asp2665Gly variant was identified in the literature in 6 out of 5644 proband chromosomes (frequency 0.001) from individuals with breast, ovarian and prostate cancers, and was identified in 1 out of 360 control chromosomes (frequency 0.003) (Borg 2010, Chenevix-Trench 2006, Edwards 2003, Evans 2008, Peixoto 2006, Soegaard 2008). The variant was also listed in the dbSNP database (ID#: rs28897745) “With Likely benign allele”, with frequencies of 0.0005 in the 1000 Genomes Project and 0.006 in the HAPMAP-TSI cohort; and was also identified in the Exome Variant Server Exome Sequencing Project with a frequency of 0.0007 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was identified in the HGMD, LOVD, ClinVar, the BIC database (26X with no clinical importance), and UMD (8X as a neutral variant). In the ClinVar database, the variant was classified as benign by the Sharing Clinical Reports Project (derived from Myriad reports) and Ambry Genetics, and as likely benign by Invitae. In UMD the variant was identified with a co-occurring pathogenic BRCA2 variant (c.3847_3848delGT (p.Val1283LysfsX2)), increasing the likelihood that the p.Asp2665Gly variant does not have clinical significance. p.Asp2665 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp2665Gly variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. One functional assay found the variant had similar levels of homology-directed repair to wild-type BRCA2 (Guidugli 2013), and analysis of a tumour showed loss of the variant, suggesting that it is neutral (Chenevix-Trench 2006 16489001). In addition, multifactorial probability-based models classify the variant as likely non-pathogenic or benign (Chenevix-Trench 2006, Guidugli 2013) and one protein likelihood ratio model predicts the variant to be neutral (Karchin 2008 19043619). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004541049	SCV004774498	likely benign	BRCA2-related disorder	2019-07-18	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).