ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4127C>G (p.Thr1376Arg) (rs80356986)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048453 SCV000076466 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132420 SCV000187512 likely benign Hereditary cancer-predisposing syndrome 2018-12-24 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586810 SCV000296484 uncertain significance not provided 2019-03-08 criteria provided, single submitter clinical testing
Counsyl RCV000031152 SCV000488586 uncertain significance Breast-ovarian cancer, familial 1 2016-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000586810 SCV000567750 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4127C>G at the cDNA level, p.Thr1376Arg (T1376R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). Using alternate nomenclature, this variant would be defined as BRCA1 4246C>G. This variant has been reported in a cohort of individuals who had undergone clinical BRCA1 analysis (Judkins 2005), and one functional study found this variant to retain homology-directed repair activity (Lu 2015). BRCA1 Thr1376Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Thr1376Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000132420 SCV000683152 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000484416 SCV000699110 uncertain significance not specified 2019-11-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4127C>G (p.Thr1376Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249098 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4127C>G has been reported in the literature in individuals affected cancer (Judkins_2005, Lu_2015). 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 (BRCA2 c.3296C>G , p.Ser1099X; internal sample), providing supporting evidence for a benign role. One publication reports experimental evidence indicating that the variant does not have a significant effect on homology-directed repair (HDR; Lu_2015). Seven ClinVar submissions (evaluation after 2014) cite the variant six times as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000031152 SCV000053752 likely benign Breast-ovarian cancer, familial 1 2010-09-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031152 SCV000144991 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353468 SCV000591494 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Thr1376Arg variant was identified in the literature in computational and functional studies (Lu 2015). The variant was also identified by our laboratory in 1 affected individual with breast cancer. Myriad classifies this variant as a polymorphism (personal communication). The variant is listed in the dbSNP database (ID#:rs80356986), but no frequency information was provided. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 2 of 102020 chromosomes (freq. 1.96x10-5) in the following populations: European (Non-Finnish) in 2 of 55610 chromosomes (freq. 3.6x10-5), but was not seen in African, East Asian, Finnish, Latino, South Asian or Other populations; this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was identified in the ClinVar database with conflicting interpretations (as variant of uncertain significance by Invitae, Ambry Genetics and BIC and as likely benign by sharing Clinical Reports Projects); GeneInsight COGR database (by 3 clinical laboratories – 2 classified it as uncertain significance and 1 as unclassified); the BIC database (2x with unknown clinical importance), and in UMD (1x with a unclassified variant). The p.Thr1376 residue is conserved in mammals, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Arginine variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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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