ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5153A>G (p.Asn1718Ser) (rs80358739)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486901 SCV000566491 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5153A>G at the cDNA level, p.Asn1718Ser (N1718S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA2 5381A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1718Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). 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 Asn1718Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570495 SCV000668574 likely benign Hereditary cancer-predisposing syndrome 2017-06-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000113388 SCV000784857 uncertain significance Breast-ovarian cancer, familial 2 2017-01-24 criteria provided, single submitter clinical testing
Invitae RCV000801842 SCV000941640 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-07-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1718 of the BRCA2 protein (p.Asn1718Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. 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: 126062). 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 serine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color Health, Inc RCV000570495 SCV001348076 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486901 SCV001469686 uncertain significance not provided 2020-02-23 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113388 SCV000146548 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000486901 SCV001549528 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 p.Asn1718Ser variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs80358739) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics; and as uncertain significance by GeneDx, Counsyl and BIC), and in UMD-LSDB (1x as unclassified variant). The variant was identified in control databases in 1 of 223044 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 1 of 27662 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asn1718 residue is not conserved in mammals and 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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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