ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3415AGT[1] (p.Ser1140del) (rs80358337)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001084973 SCV000076201 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131331 SCV000186305 likely benign Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000048188 SCV000209953 likely benign not specified 2018-01-25 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.
Counsyl RCV000112093 SCV000488758 uncertain significance Breast-ovarian cancer, familial 1 2016-06-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131331 SCV000683102 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 RCV000048188 SCV000699031 uncertain significance not specified 2019-02-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3418_3420delAGT (p.Ser1140del) results in an in-frame deletion that is predicted to remove one serine from the encoded protein. The variant allele was found at a frequency of 2.2e-05 in 276940 control chromosome (exclusively found in individuals of European descent). This frequency is not higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (2.2e-05 vs 0.001), allowing no conclusion about variant significance. However, the possibility that the variant represents a rare polymorphism cannot be excluded. c.3418_3420delAGT has been reported in the literature in individual(s) affected with- or at risk for Hereditary Breast and Ovarian Cancer (Judkins 2005). Furthermore, it has been reported in a family affected with cutaneous malignant melanoma, where it was determined not to co-segregate with the disease (Goldstein 2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported in two individuals (BRCA1 c.5263_5264insC (p.Ser1755?fs), in the BIC database and in Judkins 2005), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000203658 SCV001151332 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000112093 SCV001440669 uncertain significance Breast-ovarian cancer, familial 1 2019-01-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000203658 SCV001469380 uncertain significance not provided 2020-08-04 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112093 SCV000144759 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355449 SCV001550335 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Ser1140del variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, ARUP Laboratories, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs80358337) as “With Uncertain significance allele”; in ClinVar as likely benign by Invitae, Ambry Genetics and GeneDx, and with uncertain Significance by Counsyl and Breast Cancer Information Core. The variant was further identified in LOVD 3.0 4X with unknown significance, in UMD-LSDB database 3X as UV with no co-occurrence, in BIC Database 3X with unknown clinical significance with pending clinical classification. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser1140del variant has been found to reside in trans with known deleterious mutations. Functional studies of transgenic mice support the hypothesis that biallelic BRCA1 result in embryonic lethality. Therefore, it may be concluded that variants of unknown significance residing in trans with known deleterious mutations impart reduced risk for cancer (Judkins 2005). This variant is an in-frame deletion resulting in the removal of a serine residue at codon 1140; the impact of this alteration on BRCA1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Breast cancer type 1 susceptibility protein BRCA1 functional domain increasing the likelihood that it may have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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