ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.716A>G (p.His239Arg) (rs80357396)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112775 SCV001161506 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000925
GeneDx RCV000212160 SCV000210084 uncertain significance not specified 2017-04-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.716A>G at the cDNA level, p.His239Arg (H239R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Also reported as BRCA1 835A>G using alternate nomenclature, this variant has been observed in at least two individuals with familial breast cancer and was not observed in any of 125 unaffected controls (Dong 1998, Meindl 2002, Arnold 2002). However, in one of the families, a deleterious BRCA1 variant was identified in other relatives affected with breast cancer who did not carry BRCA1 His239Arg (Dong 1998). BRCA1 His239Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA1 His239Arg occurs at a position that is not conserved and is located in the BRD7, MB2, and p53 binding domains (Wang 1998, Zhang 1998, Chai 1999, Harte 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 His239Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000509604 SCV000608209 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-06 criteria provided, single submitter clinical testing The p.H239R variant (also known as c.716A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 716. The histidine at codon 239 is replaced by arginine, an amino acid with highly similar properties. This alteration was reported in one German female with early-onset breast cancer and a family history of early-onset breast cancer; however, her other affected relatives were found to carry a BRCA1 pathogenic mutation (Dong J et al. Hum. Genet. 1998 Aug;103:154-61). This alteration was also reported in 1/989 German breast cancer or breast/ovarian cancer families undergoing BRCA1 gene testing (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). This variant was not detected among a German control cohort of 95 females and 25 males aged over 60 years without a family history of BRCA-associated cancers (Arnold N et al. J. Chromatogr. B Analyt. Technol. Biomed. Lif. 2002 Dec;782:99-104). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000509604 SCV000911781 benign Hereditary cancer-predisposing syndrome 2016-02-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284302 SCV001470012 uncertain significance not provided 2019-12-27 criteria provided, single submitter clinical testing
Invitae RCV001339091 SCV001532811 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-03-23 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 239 of the BRCA1 protein (p.His239Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 11802209, 9760198). ClinVar contains an entry for this variant (Variation ID: 55677). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a low probability of being pathogenic (PMID: 31131967). 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112775 SCV000145669 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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