ClinVar Miner

Submissions for variant NM_007294.3(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 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 322 of the BRCA1 protein (p.Ala322Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs80357252, ExAC 0.004%). This variant has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 55767). An experimental study has shown that this missense change reduces homology-directed repair (HDR) activity compared to wild-type BRCA1 protein (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 RCV000218097 SCV000277412 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
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 RCV000218097 SCV000903583 likely benign Hereditary cancer-predisposing syndrome 2017-05-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780997 SCV000918742 uncertain significance not specified 2017-11-24 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.964G>C (p.Ala322Pro) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 3/5 in silico tools. This variant was found in 3/246158 control chromosomes (gnomAD) at a frequency of 0.0000122, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant has been detected in multiple individuals undergoing for BRCA1/2 testing in literature (Judkins_2005) and clinical databases (BIC, SCRP) without strong evidence for or against pathogenicity. Clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance (4) as well as benign(1) without evidence to independently evaluate. A study that functionally tested this variant by in vitro HDR assay showed that this variant insignificantly decreases the homologous recombination function, mean HDR activity of the mutant was 82.58% of the wild-type activity (Lu_2015). Taken together, this variant is currently classified as Variant of 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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