Submissions for variant NM_007294.4(BRCA1):c.4116_4117insTT (p.Glu1373fs)

dbSNP: rs398122682

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484969	SCV000571906	pathogenic	not provided	2016-10-03	criteria provided, single submitter	clinical testing	This insertion of two nucleotides in BRCA1 is denoted c.4116_4117insTT at the cDNA level and p.Glu1373LeufsX21 (E1373LfsX21) at the protein level. The normal sequence, with the bases that are inserted in braces, is GTGT[TT]GAGA. The insertion causes a frameshift which changes a Glutamic Acid to a Leucine at codon 1373, and creates a premature stop codon at position 21 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264474	SCV001442648	likely pathogenic	Hereditary breast ovarian cancer syndrome	2020-10-19	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4116_4117insTT (p.Glu1373LeufsX21) 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. The variant was absent in 248774 control chromosomes. To our knowledge, no occurrence of c.4116_4117insTT in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001264474	SCV003345067	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 91624). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1373Leufs*21) 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).
Ambry Genetics	RCV003162502	SCV003911974	pathogenic	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	The c.4116_4117insTT pathogenic mutation, located in coding exon 10 of the BRCA1 gene, results from an insertion of two nucleotides at position 4116, causing a translational frameshift with a predicted alternate stop codon (p.E1373Lfs*21). 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.
All of Us Research Program, National Institutes of Health	RCV000077141	SCV004840285	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2023-12-13	criteria provided, single submitter	clinical testing	This variant inserts two nucleotides in exon 11 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 BRCA1-related disorders 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.
Sharing Clinical Reports Project (SCRP)	RCV000077141	SCV000108938	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2008-12-03	no assertion criteria provided	clinical testing