ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4843G>A (p.Ala1615Thr) (rs80356987)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048677 SCV000076690 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-09 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1615 of the BRCA1 protein (p.Ala1615Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 24884479, 12142080, 25896959, 22752604, 27062684, 17453335). This variant is also known as 4962G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 55302). 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 threonine 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 RCV000130923 SCV000185835 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000586352 SCV000292821 uncertain significance not provided 2017-09-22 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4843G>A at the cDNA level, p.Ala1615Thr (A1615T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant has been previously published as BRCA1 4962G>A. This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Ladapoulou 2002, Juwle 2012, Silva 2014, D'Argenio 2015). Woods et al. (2016) demonstrated this variant to have transactivation activity similar to wildtype. BRCA1 Ala1615Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala1615Thr occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (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 Ala1615Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413325 SCV000492488 uncertain significance Neoplasm of the breast criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000235839 SCV000591542 uncertain significance not specified 2015-04-16 criteria provided, single submitter clinical testing
Color RCV000130923 SCV000683221 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586352 SCV000699178 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4843G>A (p.Ala1615Thr) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant is absent in 121412 control chromosomes. The variant has been reported in multiple HBOC patients/families in literature and in individuals undergoing BRCA1/2 testing by clinical laboratories/databases, however without strong evidence for or against pathogenicity. There are no functional studies for the variant. Multiple labs in ClinVar as well as a reputable database have classified this variant as VUS. Because of the absence of sufficient clinical information and the lack of functional studies, the variant is currently classified as a variant of uncertain significance (VUS) until additional information becomes available.
Sharing Clinical Reports Project (SCRP) RCV000083213 SCV000115287 uncertain significance Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083213 SCV000145196 uncertain significance Breast-ovarian cancer, familial 1 2002-08-23 no assertion criteria provided clinical testing

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