ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3783A>G (p.Leu1261=) (rs80356831)

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Total submissions: 9
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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) RCV000112185 SCV000578178 likely benign Breast-ovarian cancer, familial 1 2017-06-29 reviewed by expert panel curation Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02;
Invitae RCV000048332 SCV000076345 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000164014 SCV000214619 likely benign Hereditary cancer-predisposing syndrome 2014-09-09 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
GeneDx RCV000422101 SCV000515622 likely benign not specified 2017-09-29 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.
Color Health, Inc RCV000164014 SCV000688451 likely benign Hereditary cancer-predisposing syndrome 2017-09-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000422101 SCV000918693 likely benign not specified 2019-04-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3783A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. This prediction was confirmed by a functional study that used a BRCA1 minigene construct consisting of exon 10 to 12, and found that the variant does not alter splicing (Anczukow 2008). The variant allele was found at a frequency of 1.4e-05 in 276922 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (1.4e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.3783A>G, has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Wagner 1999). This report however does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.83_84delTG (p.Leu28ArgfsX12) and BRCA2 c.2957insG (p.Asn986ArgfsX2) in the UMD database), providing supporting evidence for a benign role. Three clinical diagnostic laboratories and one expert panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000112185 SCV001140542 likely benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112185 SCV000144880 benign Breast-ovarian cancer, familial 1 2004-12-30 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353488 SCV000591472 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Leu1261Leu variant was not identified in the literature. The variant was identified in dbSNP (ID: rs80356831)“With uncertain significance, untested allele”, ClinVar database, the BIC database (1X with no clinical importance), and UMD (3X as a UV variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.83_84delTG (p.Leu28ArgfsX12)), increasing the likelihood that the p.Leu1261Leu variant does not have clinical significance. The p.Leu1261Leu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site.In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

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