ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4031A>G (p.Asp1344Gly) (rs55639854)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048411 SCV000076424 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1344 of the BRCA1 protein (p.Asp1344Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer and colon cancer (PMID: 15172753, 29335924, 22655046, 26287763), and an individual affected with an unspecified cancer (PMID: 27882536). This variant is also known as 4150A>G (D1344G) in the literature. ClinVar contains an entry for this variant (Variation ID: 55077). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000132350 SCV000187439 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-10 criteria provided, single submitter clinical testing Insufficient or Conflicting Evidence
GeneDx RCV000586179 SCV000293466 uncertain significance not provided 2015-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4031A>G at the cDNA level, p.Asp1344Gly (D1344G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant has been previously published as BRCA1 4150A>G. This variant was observed in an individual with at least two first-degree relatives with breast or ovarian cancer (Hadjisavvas 2004). BRCA1 Asp1344Gly 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 Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1344Gly occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple proteins (Chen 1998, Narod 2004, Clark 2012). 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 Asp1344Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000132350 SCV000683144 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586179 SCV000699098 uncertain significance not provided 2016-11-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4031A>G (p.Asp1344Gly) variant, alternatively also known as 4150A>G, involves the alteration of a conserved nucleotide. The variant is outside of commonly known domains in BRCA1 gene (InterPro). 2/4 in silico tools used predict a benign outcome for this variant. This variant is absent in 121466 control chromosomes from ExAC. The variant has been reported in three breast and/or ovarian cancer families without strong evidence for causality (Hadjisavvas_2004, Judkins_2005, Vaca-Paniagua_2012). In one family, the family history was not highly suggestive of HBOC due to BRCA1/2 genes as there was family history of colorectal cancer and early breast cancer (Vaca-Paniagua_2012). One clinical database and a lab have classified it as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000112227 SCV000785945 uncertain significance Breast-ovarian cancer, familial 1 2018-01-18 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112227 SCV000144937 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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