ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8162T>A (p.Leu2721His) (rs80359061)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223648 SCV000274611 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-08 criteria provided, single submitter clinical testing The p.L2721H variant (also known as c.8162T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8162. The leucine at codon 2721 is replaced by histidine, an amino acid with similar properties. This variant was functionally deficient in several assays including homology-directed repair assays and a BRCA2-null mouse embryonic stem cell complementation assay (Hart SN et al. Genet. Med., 2019 01;21:71-80; Mesman RLS et al. Genet. Med. 2019; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Karchin R et al. Cancer Inform. 2008;6:203-16). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Yang H et al. Science 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000223648 SCV000683948 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-03 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001290195 SCV001478295 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.994 and an overall classification of pathogenic. (PS3_strong). Data not used in classification: There are conflicting in silico predictions of pathogenicity; AlignGVGD (class: C25), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.15). There are additional reports of this variant in ClinVar (3), BIC (1), and BRCA2 LOVD (1).
Invitae RCV001290195 SCV001535892 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-04-14 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 2721 of the BRCA2 protein (p.Leu2721His). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52513). This variant has been reported to affect BRCA2 protein function (PMID: 19043619, 29394989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113878 SCV000147285 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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