Submissions for variant NM_000059.4(BRCA2):c.7102T>G (p.Leu2368Val)

gnomAD frequency: 0.00004  dbSNP: rs397507382

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132508	SCV000187604	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206651	SCV000261841	benign	Hereditary breast ovarian cancer syndrome	2025-01-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000031666	SCV000487804	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001711136	SCV000512384	likely benign	not provided	2020-06-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21218378, 26689913, 28508593, 29146900, 30093976, 31825140)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000445338	SCV000695039	benign	not specified	2019-05-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7102T>G (p.Leu2368Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.8e-05 in 282366 control chromosomes, exclusively found within the East Asian subpopulation with a frequency of 0.0011 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.7102T>G, has been reported in the literature in individuals affected with breast cancer, but without evidence for causality (Carney_2010, Chan_2018). In addition, co-occurrences with another pathogenic BRCA2 variant have been reported (BRCA2 c.7878G>A (p.Trp2626X); in Carney_2010 and in our internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant a VUS (1x), Likely benign (2x) and Benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000132508	SCV000910908	benign	Hereditary cancer-predisposing syndrome	2016-12-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132508	SCV002531839	likely benign	Hereditary cancer-predisposing syndrome	2021-12-06	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV001711136	SCV003830134	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492318	SCV004240348	likely benign	Breast and/or ovarian cancer	2022-09-20	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000445338	SCV005090053	likely benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031666	SCV000054273	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-11-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353652	SCV000592098	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Leu2368Val variant was identified in the literature in an individual with breast cancer (Carney 2010). The variant was identified in co-occurrence with a pathogenic BRCA2 variant (p.Trp2626X) in this individual, increasing the likelihood that the p.Leu2368Val variant may not have clinical significance. The variant was also identified in dbSNP (ID: rs397507382) “With Likely Benign allele”, and in the Clinvar database (classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (derived from Myriad reports); classified as likely benign by Ambry Genetics). The variant occurs outside of the splicing consensus sequence and five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Leu2368 residue is not conserved in mammals and the variant amino acid valine (Val) is present in rat, increasing the likelihood that this variant does not have clinical significance. 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. 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250491	SCV002520828	likely benign	Familial cancer of breast		no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004532455	SCV004712007	likely benign	BRCA2-related disorder	2023-09-11	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).