ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3713C>T (p.Pro1238Leu) (rs28897688)

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Total submissions: 12
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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) RCV000031124 SCV000244346 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 = 0.0000000194
Invitae RCV000048297 SCV000076310 benign Hereditary breast and ovarian cancer syndrome 2017-12-27 criteria provided, single submitter clinical testing
Counsyl RCV000031124 SCV000154023 likely benign Breast-ovarian cancer, familial 1 2014-03-06 criteria provided, single submitter literature only
GeneDx RCV000159880 SCV000209956 likely benign not specified 2017-09-19 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 RCV000162659 SCV000213099 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159880 SCV000591466 benign not specified 2014-11-17 criteria provided, single submitter clinical testing
Color RCV000162659 SCV000683125 likely benign Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034743 SCV000699063 benign not provided 2017-04-06 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3713C>T (p.Pro1238Leu) variant causes a missense change (ACMG BP1) involving the alteration of a non-conserved nucleotide. Variant is not in any known functional domain of the protein. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest has been found in a large, broad control population, ExAC in 21/122536 control chromosomes at a frequency of 0.0001714, predominantly observed in the European (Finnish) subpopulation at a frequency of 0.001059 (7/6612). This frequency is slightly higher than the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin (BS1). The variant has been reported in multiple affected individuals without strong evidence for causality. However, this variant has been reported to co-occur with deleterious mutations in BRCA1 gene (c.5266dupC/p.Gln1756fsX74; reported as 5385insC/ and BRCA1 c.4533_4534delCA) (ACMG BP2) in two individuals suggesting a likely benign nature of this variant (Abkevich_J Med Genet_2004). This is also supported by a functional study (Lu_BRCA1&2_Nat Comm_2015) where HDR analysis in 2/3 cases showed no significant change from WT (ACMG BS3). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign (ACMG BP6). These evidences support the classification of this variant as benign based upon ACMG guidelines (BP1, BP2, BP6, BS1, and BS3). Taken together, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770740 SCV000902223 likely benign Breast and/or ovarian cancer 2017-01-16 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034743 SCV000043165 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031124 SCV000053722 benign Breast-ovarian cancer, familial 1 2007-10-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031124 SCV000144847 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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