ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7102T>G (p.Leu2368Val) (rs397507382)

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Total submissions: 8
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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: 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 RCV000206651 SCV000261841 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000031666 SCV000487804 uncertain significance Breast-ovarian cancer, familial 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 Health, Inc RCV000132508 SCV000910908 benign Hereditary cancer-predisposing syndrome 2016-12-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031666 SCV000054273 benign Breast-ovarian cancer, familial 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.

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