ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6458C>T (p.Pro2153Leu) (rs276174873)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131036 SCV000185966 uncertain significance Hereditary cancer-predisposing syndrome 2013-10-03 criteria provided, single submitter clinical testing <span style="font-family:arial,sans-serif">The <span style="font-family:arial,sans-serif">p.P2153L variant (also known as c.6458C>T and 6686C>T), located in coding exon 10 of the <span style="font-family:arial,sans-serif">BRCA2 gene, results from a C to T substitution at nucleotide position 6458. The proline at codon 2153 is replaced by leucine, an amino acid with similar properties. <span style="font-family:arial,sans-serif">This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be benign and tolerated by PolyPhen and SIFT <span style="font-family:arial,sans-serif">in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000218559 SCV000278869 uncertain significance not provided 2016-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6458C>T at the cDNA level, p.Pro2153Leu (P2153L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 6686C>T. This variant has not, to our knowledge, been published in the literature as pathogenic germline variant or benign polymorphism. However, it has been reported as a somatic variant in cutaneous squamous cell carcinoma (Li 2015). BRCA2 Pro2153Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Pro2153Leu occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Pro2153Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131036 SCV000903445 likely benign Hereditary cancer-predisposing syndrome 2015-11-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193723 SCV001362779 uncertain significance not specified 2019-02-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6458C>T (p.Pro2153Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-06 in 224676 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6458C>T in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV001306721 SCV001496102 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-28 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2153 of the BRCA2 protein (p.Pro2153Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52109). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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) RCV000113594 SCV000146862 not provided Breast-ovarian cancer, familial 2 no assertion provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000218559 SCV001553112 uncertain significance not provided no assertion criteria provided clinical testing

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