Submissions for variant NM_000059.4(BRCA2):c.1395A>C (p.Val465=)

gnomAD frequency: 0.00026  dbSNP: rs11571641

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112916	SCV000579057	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-06-29	reviewed by expert panel	curation	Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/).
Invitae	RCV000043797	SCV000071810	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000173627	SCV000167333	benign	not specified	2014-03-11	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.
Ambry Genetics	RCV000162500	SCV000212888	likely benign	Hereditary cancer-predisposing syndrome	2014-08-13	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.
Counsyl	RCV000112916	SCV000220253	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-04-17	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000173627	SCV000224754	likely benign	not specified	2014-07-21	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000112916	SCV000267745	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000043797	SCV000576433	likely benign	Hereditary breast ovarian cancer syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000173627	SCV000586928	benign	not specified	2017-04-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162500	SCV000683421	benign	Hereditary cancer-predisposing syndrome	2015-04-22	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000112916	SCV000743260	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-31	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000112916	SCV000744411	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755857	SCV000883472	benign	not provided	2023-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000755857	SCV001148974	likely benign	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000173627	SCV002070635	likely benign	not specified	2022-01-20	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162500	SCV002533231	likely benign	Hereditary cancer-predisposing syndrome	2021-04-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000173627	SCV002550278	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490599	SCV002804278	likely benign	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-02-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492345	SCV004240292	likely benign	Breast and/or ovarian cancer	2022-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952469	SCV004767519	likely benign	BRCA2-related condition	2019-03-05	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)	RCV000112916	SCV000145864	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	1999-12-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000173627	SCV000591742	benign	not specified		no assertion criteria provided	clinical testing	The BRCA2 p.Val465Val variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict the abolishment of an existing splice site or the creation of a new splice site, and a splicing minigene assay found the variant did not have an effect on splicing (Théry 2011). The variant was identified in the literature in 2 of 8048 proband chromosomes from individuals or families with breast or ovarian cancer; however control chromosomes were not evaluated in this study thus the prevalence of the variant in the general population could not be determined (van der Hout 2006). Another variant with the same synonymous amino acid change but a different nucleotide change (c.1395A>T) was identified in one individual with breast cancer in a study by Evans (2008); however, control chromosomes were not included in this study. The p.Val465Val variant was identified in the NIH Polymorphism Discovery Resource (NIHPDR) PDR90 cohort in 1 of 180 chromosomes (frequency: 0.006), and in the Exome Variant Server Exome Sequencing Project in 4 of 13006 European American alleles (frequency 0.0003), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The variant was also identified in dbSNP (ID: rs11571641) “With uncertain allele”, HGMD, LOVD, the ClinVar database (classified as benign by Invitae and GeneDx), the BIC database (1X with unknown clinical importance), and UMD (25X as a neutral variant). In UMD the variant was identified with three different co-occurring pathogenic BRCA2 variants and one pathogenic BRCA1 variant, increasing the likelihood that the p.Val465Val variant does not have clinical significance. Furthermore, Myriad classifies this as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000112916	SCV000733230	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000755857	SCV001905688	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000755857	SCV001952941	likely benign	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000112916	SCV004244216	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing