Submissions for variant NM_000059.4(BRCA2):c.9234C>T (p.Val3078=)

gnomAD frequency: 0.00002  dbSNP: rs587782428

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	RCV004567137	SCV004101449	benign	BRCA2-related cancer predisposition	2024-06-11	reviewed by expert panel	curation	The c.9234C>T variant in BRCA2 is a synonymous variant (p.Val3078=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 synonymous (silent) variant is within a key functional domain, and SpliceAI predictor score of 0.00 suggests that the variant has no impact on splicing (score threshold <0.10) (BP4 met). This is a synonymous (silent) variant, and mRNA experimental analysis indicates small or no impact on splicing (PMIDs: 31143303, 20215541 and pers comm E Velasco, Ambry internal contributor), considered strong evidence against pathogenicity (BP7_Strong (RNA)). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 0.055 (based on Family History LR=0.055), within the thresholds for Moderate benign evidence (LR >=0.05 & <0.23) (BP5_Moderate met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP4, BP7_Strong (RNA), BP5_Moderate).
Ambry Genetics	RCV000131482	SCV000186469	likely benign	Hereditary cancer-predisposing syndrome	2020-04-07	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.
Invitae	RCV001083240	SCV000259605	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131482	SCV000684038	likely benign	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000608709	SCV000695219	likely benign	not specified	2020-11-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000608709	SCV000730936	benign	not specified	2015-09-14	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.
Counsyl	RCV000495698	SCV000785176	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-05-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590584	SCV000889177	likely benign	not provided	2021-08-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000495698	SCV004846141	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355135	SCV001549924	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val3078= variant was identified in 2 of 2180 proband chromosomes (frequency: 0.0009) from individuals or families with breast or ovarian cancer (Sanz 2010, Schenkel 2016). The variant was also identified in dbSNP (ID: rs587782428) as “With Uncertain significance allele”, ClinVar (8x as benign, likely benign and uncertain significance by ENIGMA, Color, Integrated Genetics, GeneDx, Counsyl, Quest, Ambry Genetic, Invitae) and LOVD 3.0 (2x as VUS and likely benign).The variant was not identified in UMD-LSDB. The variant was also identified by our laboratory in 1 individual with BRCA. The variant was identified in control databases in 3 of 276678 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 34360 chromosomes (freq: 0.00003), European Non-Finnish in 2 of 126488 chromosomes (freq: 0.000016), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Val3078= 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) do not predict a difference in splicing. However, in a study by (Sanz 2010), bioinformatics programs predicted the disruption of an exonic splicing enhancer and the creation of exonic splicing silencers; in addition, mRNA analysis of the variant in this study showed partial exon 24 skipping, with a predicted partial truncation of protein product. In this same study the variant was identified in a patient with a co-occurring BRCA1 c.4165_4166delAG pathogenic variant providing conflicting evidence. 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000590584	SCV001928470	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590584	SCV001952297	likely benign	not provided		no assertion criteria provided	clinical testing