ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.995G>A (p.Arg332Gln) (rs80357464)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195399 SCV000077229 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 332 of the BRCA1 protein (p.Arg332Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs80357464, ExAC 0.009%). This variant has been reported in individuals affected with breast cancer (PMID: 25337278, 16826315, 24916970, 21520333). However, in one of these individuals, a pathogenic allele was also identified in BRCA1 (PMID: 21520333), which suggests that this c.995G>A variant was not the primary cause of disease. This variant is also known as 1227thG>A and 1114G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55776). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000129927 SCV000184745 likely benign Hereditary cancer-predisposing syndrome 2018-01-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,in silico models in agreement (benign)
GeneDx RCV000049216 SCV000210096 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.995G>A at the cDNA level, p.Arg332Gln (R332Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGG>CAG). Using alternate nomenclature, this variant would be defined as BRCA1 1114G>A or 1227G>A. This variant was observed in at least one Portuguese breast and/or ovarian cancer family and in at least two Chinese breast cancer patients (Peixoto 2006, Peixoto 2014, Sun 2014). BRCA1 Arg332Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg332Gln is located in a region known to interact with multiple other proteins (Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Arg332Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000111525 SCV000488037 uncertain significance Breast-ovarian cancer, familial 1 2015-12-22 criteria provided, single submitter clinical testing
Mendelics RCV000195399 SCV000839292 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129927 SCV000903088 likely benign Hereditary cancer-predisposing syndrome 2016-10-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780998 SCV000918743 uncertain significance not specified 2017-10-13 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.995G>A (p.Arg332Gln) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). The Arg to Gln alteration predicted not to affect protein function since Gln at this position is frequently found in other vertebrates, moreover studies based on comparative evolutionary methods also support this prediction (Fleming 2003, Abkevich 2004, Pavlicek 2004). The variant was found not to affect splicing in an in vitro fuctional study (Anczukow 2008). This variant was found in 8/246216 control chromosomes at a frequency of 0.0000325, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has been reported in individuals affected by BrC or OvC (Peixoto 2006, Sun 2014, Shi 2017), however without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111525 SCV000143976 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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