ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3888_3890TTC[1] (p.Ser1298del) (rs80358339)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236417 SCV000292520 uncertain significance not provided 2015-12-09 criteria provided, single submitter clinical testing This deletion of three nucleotides in BRCA1 is denoted c.3891_3893delTTC at the cDNA level and p.Ser1298del at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTTC[TTC]ACAG. This in frame deletion of a single Serine residue in exon 10 occurs at a position that is conserved across species and is located within the SCD domain and the region of interaction with ATM, CHEK2 and CDK2 (Narod 2004, Clark 2012). Functional studies by Bouwman et al. (2013) have suggested that BRCA1 Ser1298del, also known as Ser1297del, is neutral based on insensitivity to cisplatin and ability to support growth similar to controls in BRCA1-deficient mouse embryonic stem cells. Alternatively, multiple splicing models do not predict the natural splice donor site, thus a splicing effect cannot be ruled out. Since in frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 Ser1298del to be a variant of uncertain significance.
Ambry Genetics RCV001021370 SCV001182979 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001236117 SCV001408829 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-07-31 criteria provided, single submitter clinical testing This variant, c.3891_3893delTTC, results in the deletion of 1 amino acid of the BRCA1 protein (p.Ser1298del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in at least one family affected with breast and ovarian cancer (PMID: 28283652, 18273839). This variant is also known as 4010delTTC, S1297del in the literature. ClinVar contains an entry for this variant (Variation ID: 55038). Experimental studies have shown that BRCA1 protein containing this amino acid deletion restores cisplatin sensitivity in BRCA1-null mouse embryonic stem cells (PMID: 23867111). 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112208 SCV000144909 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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