ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.685del (p.Ser229fs) (rs80357824)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112771 SCV000299474 pathogenic Breast-ovarian cancer, familial 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Invitae RCV000049094 SCV000077107 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-27 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the BRCA1 mRNA (c.685delT), causing a frameshift at codon 229. This creates a premature translational stop signal (p.Ser229Leufs*5) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in the literature in an individual with breast cancer (PMID: 27553291). For these reasons, this variant has been classified as Pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112771 SCV000326391 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000112771 SCV000487837 likely pathogenic Breast-ovarian cancer, familial 1 2015-11-21 criteria provided, single submitter clinical testing
GeneDx RCV000486620 SCV000568432 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This deletion of one nucleotide in BRCA1 is denoted c.685delT at the cDNA level and p.Ser229LeufsX5 (S229LfsX5) at the protein level. Using alternate nomenclature this variant would be defined as BRCA1 804delT. The normal sequence, with the base that is deleted in brackets, is ATTT[delT]CTGA. The deletion causes a frameshift which changes a Serine to a Leucine at codon 229, and creates a premature stop codon at position 5 of the new reading frame. It is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.685delT has been observed two individuals with triple negative breast cancer (Rashid 2016). We consider this variant to be pathogenic.
Color Health, Inc RCV001178319 SCV001342720 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049094 SCV001360725 pathogenic Hereditary breast and ovarian cancer syndrome 2019-09-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.685delT (p.Ser229LeufsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 246068 control chromosomes (gnomAD). c.685delT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Rashid_2016, Singh_2018, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) including one expert panel (ENIGMA) cite the variant as pathogenic (4x)/likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112771 SCV000145664 pathogenic Breast-ovarian cancer, familial 1 1999-12-22 no assertion criteria provided clinical testing

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