ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4963T>C (p.Ser1655Pro) (rs1057518639)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000414437 SCV000492478 uncertain significance Breast neoplasm criteria provided, single submitter research
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000675184 SCV000800819 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing Data used in classification: The variant was observed in 2 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (2/16,600 in familial cases against 0/63,369 GNOMAD NFE controls passoc=0.005 pexact= 0.04 (PS4). 3 additional families have been identified in the UK (not included in the previous dataset). The variant is also absent in the remainder of the GNOMAD populations (75,263 individuals) (PM2). Located in BRCT1 domain (PM1_supporting). Non-functional using saturation genome editing in haploid BRCA1 cellular model (Findlay et al 2018, BioARchiv) (PS3_mod). BRCA1 c.4963T>A p.Ser1655Thr independently established as pathogenic (PM5). Additional Information (not included in classification): Predicted deleterious on SIFT but benign on Align GVGD and Polyphen. For substitutions to proline, Align-GVGD is known not to score properly if the variant is in an alpha helix (published data and personal communication, Tavtigian).
Mendelics RCV000675184 SCV000839225 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000989875 SCV001140498 likely pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000675184 SCV001233342 pathogenic Hereditary breast and ovarian cancer syndrome 2019-10-30 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 1655 of the BRCA1 protein (p.Ser1655Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 23469205, 29868112). ClinVar contains an entry for this variant (Variation ID: 373826). This variant has been reported to affect BRCA1 protein function (PMID: 12496477, 30209399). This variant is also known as T5082C in the literature. This variant disrupts the p.Ser1655 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15133502, 15133503, 19200354, 19563646, 24249303, 27767231). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Brotman Baty Institute,University of Washington RCV000989875 SCV001238724 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357954 SCV001553567 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser1655Pro variant was identified in the literature however the frequency of this variant in an affected population was not provided (Flower 2015, Findlay 2018). The variant was also identified in dbSNP (ID: rs1057518639) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by one submitter; as likely pathogenic by Mendelics Analise Genomica; as pathogenic by Cancer Variant Interpretation Group UK). The variant was not identified in LOVD 3.0, UMD-LSDB, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser1655 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant was identified in DNA methylation profiling to assess pathogenicity of BRCA1 unclassified variants in breast tumor DNA samples and had posterior probability using methylation of only 0.39565 (Flower 2015). 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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