ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4009G>C (p.Asp1337His) (rs886041144)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000259337 SCV000329128 uncertain significance not provided 2016-09-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4009G>C at the cDNA level, p.Asp1337His (D1337H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAC>CAC). Using alternate nomenclature, this variant would be defined as BRCA1 4128G>C. BRCA1 Asp1337His has been observed in at least one individual with a history of breast cancer (Bolognesi 2014). This variant 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 Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1337His occurs at a position that is not conserved and is located within the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Chen 1998). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Asp1337His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637752 SCV000759227 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 1337 of the BRCA1 protein (p.Asp1337His). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25415331). ClinVar contains an entry for this variant (Variation ID: 279705). 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.

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