Submissions for variant NM_007294.4(BRCA1):c.4655_4658del (p.Tyr1552fs)

dbSNP: rs80357561

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077581	SCV000300151	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-08	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
GeneDx	RCV000074597	SCV000108682	pathogenic	not provided	2020-11-10	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual referred for hereditary cancer testing (LaDuca 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.4774_4777delACTT; This variant is associated with the following publications: (PMID: 28152038, 16267036, 32719484)
Ambry Genetics	RCV000131826	SCV000186881	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The c.4655_4658delACTT pathogenic mutation, located in coding exon 13 of the BRCA1 gene, results from a deletion of 4 nucleotides at nucleotide positions 4655 to 4658, causing a translational frameshift with a predicted alternate stop codon (p.Y1552Cfs*6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Counsyl	RCV000077581	SCV000488608	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2016-05-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588044	SCV000699162	pathogenic	Hereditary breast ovarian cancer syndrome	2021-12-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4655_4658delACTT (p.Tyr1552CysfsX6) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (example: c.4689C>G|p.Tyr1563X; c.4754_4755delCA|p.Pro1585ArgfsX36). The variant was absent in 251230 control chromosomes. c.4655_4658delACTT has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Judkins_2005, Zheng_2018, BIC database). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters, including one expert panel (Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)), have assessed the variant since 2014: five have classified it as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000131826	SCV001354776	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 14 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 30130155). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000588044	SCV001590573	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1552Cysfs*6) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with BRCA1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 55252). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000077581	SCV004817643	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-07-19	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 14 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual who underwent cancer genetic testing (PMID: 16267036). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077581	SCV000109384	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-06-30	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077581	SCV000145140	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing