ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3842A>C (p.Gln1281Pro)

gnomAD frequency: 0.00004  dbSNP: rs80357483
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000112198 SCV000488929 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-07-21 criteria provided, single submitter clinical testing
GeneDx RCV000484233 SCV000565975 uncertain significance not provided 2015-09-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3842A>C at the cDNA level, p.Gln1281Pro (Q1281P) at the protein level, and results in the change of a Glutamine to a Proline (CAG>CCG). Using alternate nomenclature, this variant has been previously published as BRCA1 3961A>C. This variant has been reported in at least one individual undergoing BRCA1/2 analysis at a commercial laboratory and was predicted to abolish the kinase binding motif resulting in the loss of the phosphorylation site at Ser1280 (Judkins 2005, Tram 2013). BRCA1 Gln1281Pro was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamine and Proline differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gln1281Pro occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Gln1281Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000775153 SCV000909290 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing
Invitae RCV001369992 SCV001566452 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1281 of the BRCA1 protein (p.Gln1281Pro). This variant is present in population databases (rs80357483, gnomAD 0.004%). This missense change has been observed in individual(s) with low grade glioma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 55025). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000775153 SCV002624661 likely benign Hereditary cancer-predisposing syndrome 2022-04-18 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000775153 SCV003851301 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003478991 SCV004223754 likely benign not specified 2023-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3842A>C (p.Gln1281Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251134 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3842A>C has been reported in the literature as a VUS in settings of clinical testing and in cohorts of individuals with adult cancers and the The Cancer Genome Atlas (TCGA) cohort (example, Judkins_2005, Huang_2018, Yang_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on homology directed repair (HDR) (example, Lu_2015). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29625052, 16267036, 26689913, 23704879, 36451132). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=2; VUS, n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112198 SCV000144895 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing

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