ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5455C>T (p.Pro1819Ser) (rs80358768)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113432 SCV000244458 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.00000012
Invitae RCV001083845 SCV000072676 benign Hereditary breast and ovarian cancer syndrome 2020-11-26 criteria provided, single submitter clinical testing
GeneDx RCV000587294 SCV000108626 likely benign not provided 2020-09-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 24323938, 20589654, 11556836, 21990134, 26182991, 28324225, 28525389, 26119842, 18824701)
Ambry Genetics RCV000162505 SCV000212894 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000415168 SCV000492705 likely benign Breast carcinoma 2015-09-21 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282635 SCV000602804 benign none provided 2019-09-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162505 SCV000683706 likely benign Hereditary cancer-predisposing syndrome 2015-07-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587294 SCV000694871 benign not provided 2016-06-22 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5455C>T (p.Pro1819Ser) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. A multifactorial probability based model showed this variant is neutral (Lindor_2012). This variant was found in 23/121138 control chromosomes at a frequency of 0.0001899, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been found in numerous individuals who also carry a pathogenic BRCA variant, suggesting this variant is unlikely to associate with the disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000162505 SCV000747807 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001113816 SCV001271612 uncertain significance Fanconi anemia, complementation group D1 2017-06-07 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina RCV000113432 SCV001271613 likely benign Breast-ovarian cancer, familial 2 2017-06-07 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587294 SCV001746173 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646399 SCV001854837 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA2) RCV000113432 SCV000146616 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113432 SCV000189309 benign Breast-ovarian cancer, familial 2 2008-09-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000113432 SCV000591969 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Pro1819Ser variant was identified in 1 of 228 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer (Spearman 2008). The variant was also identified in dbSNP (ID: rs80358768) NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, as a likely benign variant by GeneDx and as uncertain significance by BIC), Gene Insight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, by a clinical laboratory as ‘not classified’), the BIC database (40X with unknown clinical importance) and UMD (4X as a likely neutral variant). This variant was identified by our laboratory in one individual where a second co-occuring pathogenic variant was identified in BRCA1 (c.843_846delCTCA, p.Ser282TyrfsX15), increasing the likelihood this variant does not have clinical significance. The variant was identified by the Exome Variant Server project in 1 of 8600 European American (frequency: 0.0001), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Pro1819 residue is not 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. In addition, two in silico studies using either a multifactorial-likelihood model or tumour histopathology characteristics predict the variant to be neutral (Easton 2007, Spearman 2008) increasing the likelihood this variant may not have clinical significance. In summary, based on the above information, this variant is classified as benign.

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