ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3662C>A (p.Ser1221Tyr) (rs397507313)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160066 SCV000210319 uncertain significance not provided 2014-09-04 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3662C>A at the cDNA level, p.Ser1221Tyr (S1221Y) at the protein level, and results in the change of a Serine to a Tyrosine (TCT>TAT). This variant has been identified in at least one individual with a personal and family history of breast cancer and was absent from unaffected controls (Meindl 2002). BRCA2 Ser1221Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Tyrosine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Ser1221Tyr occurs at a position that is conserved across species and is located in BRC2, one of the BRC repeats of BRCA2 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, it is unclear whether BRCA2 Ser1221Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000698137 SCV000826780 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-25 criteria provided, single submitter clinical testing This sequence change replaces serine with tyrosine at codon 1221 of the BRCA2 protein (p.Ser1221Tyr). The serine residue is moderately conserved and there is a large physicochemical difference between serine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 11802209). ClinVar contains an entry for this variant (Variation ID: 37851). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably 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.
Color RCV000772742 SCV000906066 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031432 SCV000054037 uncertain significance Breast-ovarian cancer, familial 2 2010-01-15 no assertion criteria provided clinical testing

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