ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.964G>C (p.Ala322Pro) (rs80357252)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049206 SCV000077219 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000218097 SCV000277412 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing The p.A322P variant (also known as c.964G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 964. The alanine at codon 322 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in a patient with renal cell carcinoma, and a functional comparison showed that this alteration displayed 82% homology-directed repair (HDR) function in comparison to wild type BRCA1 (Lu C et al. Nat Commun 2015; 6:10086). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000483940 SCV000566751 uncertain significance not provided 2018-09-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.964G>C at the cDNA level, p.Ala322Pro (A322P) at the protein level, and results in the change of an Alanine to a Proline (GCT>CCT). Using alternate nomenclature, this variant would be defined as BRCA1 1083G>C. This variant was observed in at least one individual undergoing clinical BRCA1 screening, with the clinical significance defined as undetermined (Judkins 2005). It was also identified in both tumor and normal surrounding tissue from an individual with clear cell renal cell cancer, with functional studies showing a decrease in homology-directed repair activity (Lu 2015). BRCA1 Ala322Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in a region known to interact with multiple proteins (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 Ala322Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000218097 SCV000903583 likely benign Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780997 SCV000918742 uncertain significance not specified 2020-08-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.964G>C (p.Ala322Pro) 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 8e-06 in 251394 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.964G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Judkins_2005, Mu_2016, Abulkhair_2018). These reports 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. The most pronounced variant effect results in >50%-90% of normal activity (Lu_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=2, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483940 SCV001133659 uncertain significance not provided 2019-03-13 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083228 SCV000115302 benign Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083228 SCV000143967 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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