Submissions for variant NM_000059.4(BRCA2):c.7534C>T (p.Leu2512Phe)

gnomAD frequency: 0.00002  dbSNP: rs80358980

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000113773	SCV001161533	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 = 0.000428
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085013	SCV000073252	benign	Hereditary breast ovarian cancer syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130690	SCV000185577	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	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.
GeneDx	RCV001705702	SCV000210428	likely benign	not provided	2021-03-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24489791, 31131967, 19043619, 21120943, 27914478, 12228710, 25964535, 10923033, 18951461, 28283652, 30254663, 28288110, 30588330, 30199306, 32994724, 33067490)
Counsyl	RCV000113773	SCV000220890	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-11-14	criteria provided, single submitter	literature only
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001705702	SCV000600754	uncertain significance	not provided	2021-07-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130690	SCV000683885	likely benign	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212260	SCV000695076	uncertain significance	not specified	2019-12-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7534C>T (p.Leu2512Phe) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 348928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7534C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality (e.g. Zuntini_2018, Shimelis_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant(s) have been reported (BRCA1 c.4760C>G, p.Ser1587X), providing supporting evidence for a benign role (UMD database). In addition, several computational and multifactorial models suggest this variant as neutral or likely benign (Whiley_2014, Karchin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters cite the variant as benign/likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001705702	SCV002010329	benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149690	SCV003838176	uncertain significance	Breast and/or ovarian cancer	2022-05-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001705702	SCV004234876	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing
North East Yorkshire Genomic Laboratory Hub	RCV003493425	SCV004242317	likely pathogenic	Familial cancer of breast		criteria provided, single submitter	not provided
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212260	SCV004243063	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001705702	SCV004701366	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001085013	SCV005205757	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-22	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113773	SCV000147115	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000113773	SCV000297553	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2006-10-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356168	SCV001551258	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu2512Phe variant was identified in 3 of 100,182 proband chromosomes (frequency: 0.00003) from individuals or families with breast or ovarian cancer (Caux-Moncoutier 2011, Maistro 2016, Shimelis 2017) and in 1 of 97,576 control chromosomes (frequency: 0.00001) from healthy individuals (Shimelis 2017). The variant was also identified in dbSNP (ID: rs80358980) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Counsyl; and as uncertain significance by Ambry Genetics and five other submitters), LOVD 3.0 (4x), UMD-LSDB (8x as unclassified variant), BIC Database (4x as unknown significance), and ARUP Laboratories (Likely not pathogenic or of little clinical significance) databases. The variant was identified in control databases in 6 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5484 chromosomes (freq: 0.0002), Latino in 3 of 33576 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 111612 chromosomes (freq: 0.000009), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while it was not observed in the African, Ashkenazi Jewish, East Asian, or European Finnish populations. One clinical laboratory reports identifying this variant as homozygous variant in an individual with no personal or family history of Fanconi anemia. The p.Leu2512 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001705702	SCV001932515	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212260	SCV001953576	benign	not specified		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113773	SCV004228438	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Supporting)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
PreventionGenetics, part of Exact Sciences	RCV004537205	SCV004756513	likely benign	BRCA2-related disorder	2020-07-13	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).