ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3711A>G (p.Ile1237Met) (rs80357388)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048295 SCV000076308 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1237 of the BRCA1 protein (p.Ile1237Met). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with personal and/or family history of breast and/or ovarian cancer (PMID: 24884479, 25896959, 27062684) and an individual affected with papillary serous carcinoma of the peritoneum (PMID: 10728699). This variant is also known as 3830A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 54973). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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 RCV000130925 SCV000185837 likely benign Hereditary cancer-predisposing syndrome 2018-06-08 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413857 SCV000492486 uncertain significance Neoplasm of the breast criteria provided, single submitter research
GeneDx RCV000588267 SCV000569036 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3711A>G at the cDNA level, p.Ile1237Met (I1237M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 3830A>G. This variant was observed in at least two women with breast cancer as well as in one individual with nasopharyngeal cancer (Silva 2014, D?Argenio 2015, Fountzilas 2017). BRCA1 Ile1237Met was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Methionine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ile1237Met occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ile1237Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000487176 SCV000591465 uncertain significance not specified 2014-09-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000487176 SCV000605849 uncertain significance not specified 2016-10-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588267 SCV000699062 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3711A>G (p.Ile1237Met) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed . This variant was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in affected individuals via publications. Multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS or Likely Benign. Because of the absence strong clinical information and the lack of functional studies, the variant has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color RCV000130925 SCV000911437 likely benign Hereditary cancer-predisposing syndrome 2016-08-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112161 SCV001284946 uncertain significance Breast-ovarian cancer, familial 1 2018-01-13 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) RCV000112161 SCV000144845 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing

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