ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000416524 SCV000072783 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-04 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.
Ambry Genetics RCV000129417 SCV000184187 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Other data supporting benign classification;Other strong data
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Color Health, Inc RCV000129417 SCV000903215 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113490 SCV000146708 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000113490 SCV000592004 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Ser1946Pro variant was identified in 3 of 2172 proband chromosomes (frequency: 0.001) from Chinese and Taiwanese individuals or families with breast disease (benign and cancerous) and ovarian cancer, and was not identified in 638 control chromosomes from healthy individuals (Suter 2004, Chao 2016). The variant was found in 2 sisters with ovarian cancer, who had a history of familial malignancies (pancreatic and colon cancer) but segregation studies were not done (Chao 2016); Suter (2004) identified the variant in an individual with benign breast disease. The variant was also identified in dbSNP (ID: rs80358811) “With Uncertain significance allele”, ClinVar (classified as uncertain significance (2016); submitters: Invitae, Ambry Genetics, GeneDx, BIC, and Laboratory Corporation of America), Clinvitae (4x), LOVD 3.0 (1x), UMD-LSDB (2x as 3-UV), and BIC Database (1x, clinical importance unknown, classification pending) and was not identified in GeneInsight – COGR (unavailable), Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 8 of 276890 chromosomes at a frequency of 0.00003 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 2 of 24018 chromosomes (frequency: 0.00008) and East Asian in 6 of 18868 chromosomes (frequency: 0.0003). The p.Ser1946 residue is not conserved in mammals and four out of five 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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