ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3713C>T (p.Pro1238Leu) (rs28897688)

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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) 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 RCV001083575 SCV000076310 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 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 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.
Color Health, Inc RCV000162659 SCV000683125 likely benign Hereditary cancer-predisposing syndrome 2015-04-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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
Illumina Clinical Services Laboratory,Illumina RCV000031124 SCV001284945 likely benign Breast-ovarian cancer, familial 1 2017-04-27 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353836 SCV000591466 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Pro1238Leu variant was identified in 3 of 4198 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer (Akbari 2011, Johnston 2012, Rummel 2013). The variant was also identified in dbSNP (ID: rs28897688) “With Uncertain significance,other allele”, HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports; classified as likely benign by Invitae and Counsyl), GeneInsight through the Canadian Open Genetics Repository ( (1X, classified as “unclassified” by a clinical laboratory), the BIC database (42X with unknown clinical importance), and UMD (3X as a neutral variant). This variant was identified in three HAPMAP populations: HAPMAP-CEU in 1 of 224 chromosomes (frequency: 0.004), HAPMAP-JPT in 1 of 172 chromosomes (frequency: 0.006), and HAPMAP-MEX in 1 of 98 chromosomes (frequency: 0.01). The variant was also identified in two European populations within the Exome Aggregation Consortium Browser, in 13/67692 European non-Finnish alleles (frequency: 0.000192) and 7/6746 Finnish alleles (frequency: 0.001038). The presence of the variant in these populations increases the likelihood that this is a low frequency benign variant in certain populations of origin. The p.Pro1238 residue is not conserved in mammals and the variant amino acid leucine (Leu) is present in cow, increasing the likelihood that the variant does not have clinical importance. In addition, 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. An in silico study using conservation analysis suggests the variant is likely deleterious; however the was identified with a known deleterious mutation (5385insC) in a BRCA1 in the same study, increasing the likelihood the variant may not have clinical significance (Abkevich 2004). In addition, two in silico studies using multifactorial probability-based models found this variant to be neutral (Easton 2007, Lindor 2012). Furthermore, this variant was identified by our lab in an individual who had a co-occuring pathogenic variant in BRCA2 (c.5946delT, p.Ser1982ArgfsX22), increasing the likelhood that this variant is benign. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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