ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4910C>T (p.Pro1637Leu) (rs80357048)

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Total submissions: 13
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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) RCV000077589 SCV000244372 benign Breast-ovarian cancer, familial 1 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 = 0.0000627
Invitae RCV001084321 SCV000076704 benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000077589 SCV000195934 benign Breast-ovarian cancer, familial 1 2014-11-03 criteria provided, single submitter clinical testing
GeneDx RCV000048691 SCV000209980 likely benign not specified 2017-09-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000162989 SCV000213477 benign Hereditary cancer-predisposing syndrome 2014-11-18 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000048691 SCV000538456 uncertain significance not specified 2016-08-11 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Classified as benign by expert panel (8/10/15)
Color Health, Inc RCV000162989 SCV000683226 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586145 SCV000699181 benign not provided 2016-03-22 criteria provided, single submitter clinical testing Variant Summary: This variant involves alteration of a non-conserved nucleotide and 2/4 in silico tools predict a benign outcome (SNP&GO not captured here due to low reliability index). This variant was found in 3/121924 control chromosomes at a frequency of 0.0000246, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0010005). Variant has been reported in multiple affected individuals without evidence for causality. In particular, this variant is found to commonly co-occur with the BRCA1 pathogenic variant c.2457delC (internal data, BIC database, Humphrey_1997, and Tavtigian_2006), suggesting this variant of interest is in linkage disequilibrium and has been suggested to be a rare polymorphism per Humphrey_1997. In addition, multiple publications (Easton_2007, Lindor_2012 and Humphrey_1997), clinical labs, and databases (ARUP, ClinVar, Invitae, SCRP) classify the variant as benign/likely benign. Functional studies suggest that the variant acts comparably to wild-type (Humphrey_1997 and Coyne_2004). Considering all, variant is classified as Benign.
Mendelics RCV000077589 SCV001140505 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077589 SCV000109392 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077589 SCV000145207 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077589 SCV001238647 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358461 SCV001554202 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Pro1637Leu variant was identified in 1 of 858 proband chromosomes (frequency: 0.001) from individuals or families with ovarian cancer (Kanchi 2014). The variant was also identified in dbSNP (ID: rs80357048) as "With Uncertain significance, other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics and four other submitters; as likely benign by two submitters and as uncertain significance by two submitters), MutDB , LOVD 3.0 (8x), UMD-LSDB (6x as unclassified variant), BIC Database (67x with unknown significance), and in ARUP Laboratories (not pathogenic or of no clinical significance). The variant was not identified in the COGR, Cosmic, or Zhejiang University, databases. The variant was identified in control databases in 5 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 5 of 111576 chromosomes (freq: 0.00005), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Pro1637 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) do not predict a difference in splicing. The multifactorial probability based model determined the variant has posterior probability of being deleterious 6.27×10-5 and predicted to be neutral with odds of neutrality = 493 (Lindor 2012, Easton 2007). In addition, in several publications the variant observed with one or more known truncating mutations (Kanchi 2014, Tavtigian 2006), increasing the likelihood that the p.Pro1637Leu variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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