Submissions for variant NM_007294.4(BRCA1):c.4834_4835del (p.Gln1612fs)

dbSNP: rs1555580840

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000661347	SCV000783618	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2017-12-15	reviewed by expert panel	curation	Variant allele predicted to encode a truncated non-functional protein.
Ambry Genetics	RCV000510131	SCV000607911	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-20	criteria provided, single submitter	clinical testing	The c.4834_4835delCA pathogenic mutation, located in coding exon 14 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 4834 to 4835, causing a translational frameshift with a predicted alternate stop codon (p.Q1612Efs*9). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781034	SCV000918803	likely pathogenic	Hereditary breast ovarian cancer syndrome	2018-12-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4834_4835delCA (p.Gln1612GlufsX9) 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 (eg. c.5030_5033delCTAA, p.Thr1677fsX2; c.5080G>T, p.Glu1694X). The variant was absent in 246150 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4834_4835delCA in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000510131	SCV001345167	pathogenic	Hereditary cancer-predisposing syndrome	2021-01-18	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 15 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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.