ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1879G>A (p.Val627Ile) (rs80357425)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047616 SCV000075629 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 627 of the BRCA1 protein (p.Val627Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs80357425, ExAC 0.003%). This variant has been reported in individuals affected with hereditary breast and ovarian cancer (PMID: 18559594, 15235020, 29176636) and in healthy controls (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 54377), Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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 RCV000130566 SCV000185437 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-18 criteria provided, single submitter clinical testing The p.V627I variant (also known as c.1879G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1879. The valine at codon 627 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been identified in 1/830 Japanese families who underwent BRCA1/2 testing (Arai M et al. J. Hum. Genet. 2018 Apr;63:447-457). This alteration was observed in with an allele frequency of 0.00071 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00071 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0005 in 12490 male controls of Japanese ancestry​​ (Momozawa Y et al. Nat Commun. 2018 10;9:4083). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). This amino acid position is well 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.
GeneDx RCV000344730 SCV000329122 uncertain significance not provided 2016-07-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1879G>A at the cDNA level, p.Val627Ile (V627I) at the protein level, and results in the change of a Valine to an Isoleucine (GTC>ATC). Using alternate nomenclature, this variant has been published as BRCA1 1998G>A. This variant was observed in a woman with ovarian cancer (Soegaard 2008) and in an individual with a personal or family history of breast and/or ovarian cancer (Romano 2007). BRCA1 Val627Ile 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 Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val627Ile occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the DNA binding domain as well as a region known to interact with multiple 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 evidence, it is unclear whether BRCA1 Val627Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000130566 SCV000903127 likely benign Hereditary cancer-predisposing syndrome 2015-10-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000111712 SCV001285067 uncertain significance Breast-ovarian cancer, familial 1 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111712 SCV000144215 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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