ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5836T>C (p.Ser1946Pro) (rs80358811)

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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 RCV000129417 SCV000184187 likely benign Hereditary cancer-predisposing syndrome 2016-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other strong data
Breast Cancer Information Core (BIC) (BRCA2) RCV000113490 SCV000146708 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Color RCV000129417 SCV000903215 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000222466 SCV000592004 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000588442 SCV000279783 uncertain significance not provided 2018-02-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5836T>C at the cDNA level, p.Ser1946Pro (S1946P) at the protein level, and results in the change of a Serine to a Proline (TCA>CCA). This variant, also defined as 6064T>C using alternate nomenclature, has been reported in a woman with benign breast disease and in a healthy control cohort (Suter 2004, Kwong 2016); however, it has also been identified in two sisters with ovarian cancer, with the tumor from one demonstrating loss of heterozygosity at the BRCA2 locus (Chao 2016). BRCA2 Ser1946Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 binding domain (Roy 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Ser1946Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000416524 SCV000494416 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-04-17 criteria provided, single submitter clinical testing Variant Summary: The c.5836T>C is a missense variant involves a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome and calculations on whether this change will have an impact on phosphorylation of BRCA2 were not reliable (Trump, 2013). This variant was reported in 1 pt with benign breast disease and also found in control population of ExAC at a low frequency. The observed allele frequency of this variant in general population is 0.0024%, which is lower than calculated maximum disease allele frequency (0.075%) for pathogenic BRCA2 variant, therefore is not significant enough to rule out pathogenicity. Reputable dbs classify this variant as VUS. Taken all data available at this time, there is insufficient evidence to establish the clinical significance of this variant with confidence. Therefore, the classification of VUS was accepted at this time until more data become available.
Integrated Genetics/Laboratory Corporation of America RCV000588442 SCV000694906 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5836T>C (p.Ser1946Pro) variant (alternatively also known as 6064T>C) involves the alteration of a non-conserved nucleotide and is located nearby the BRC motif in the protein (InterPro, Chao_2016). 3/5 in silico tools predict benign outcome for this variant. This variant was found in 5/123618 control chromosomes including ExAC at a frequency of 0.0000404, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In literature, this variant has been found in multiple patients with HBOC including one patient with benign breast cancer. In one study, this variant was found in two siblings affected with ovarian cancer (Chao_2016). However, it was also found in other two unaffected siblings and detailed cosegregation study was not possible in the family. In another study, this variant was found in one HBOC patient who also carried another unspecified pathogenic variant. In BIC, this variant was found to co-occur with BRCA1 p.Trp1837Arg in one individual which is classified as likely pathogenic by three laboratories in ClinVar. Thus clinical findings and population frequency data are not conclusive enough for determining pathogenicity of this variant at this time. There are no published functional studies for this variant. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Unknown Significance.
Invitae RCV000416524 SCV000072783 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-30 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 1946 of the BRCA2 protein (p.Ser1946Pro). The serine residue is weakly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs80358811, ExAC 0.02%). This variant has been reported in an individual with benign breast disease (PMID: 14973102), two sisters with ovarian cancer from a single family (PMID: 27907908), two unrelated case of breast cancer (PMID: 29884136) and an individual from a family with a predisposition to breast cancer and/or ovarian cancer (PMID: 27062684). ClinVar contains an entry for this variant (Variation ID: 51948). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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