Submissions for variant NM_007294.4(BRCA1):c.4335_4338dup (p.Gln1447fs)

dbSNP: rs397509164

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000241019	SCV000300104	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048527	SCV000076540	pathogenic	Hereditary breast ovarian cancer syndrome	2022-10-12	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55172). This variant is also known as c.4338_4339insAGAA p.Gln1447Argfs*16. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22798144, 28724667, 30287823). This sequence change creates a premature translational stop signal (p.Gln1447Argfs*16) 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	RCV000167492	SCV000218350	pathogenic	Hereditary cancer-predisposing syndrome	2016-02-22	criteria provided, single submitter	clinical testing	The c.4335_4338dupAGAA pathogenic mutation, located in coding exon 11 of the BRCA1 gene, results from a duplication of AGAA at nucleotide position 4335, causing a translational frameshift with a predicted alternate stop codon. This pathogenic mutation was identified in two Korean individuals diagnosed with breast cancer and met clinical criteria for hereditary breast and ovarian cancer (HBOC) syndrome (Kim H et al. Breast Cancer Res Treat. 2012 Aug;134(3):1315-26). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000241019	SCV000325923	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000478176	SCV000566755	pathogenic	not provided	2016-12-06	criteria provided, single submitter	clinical testing	This duplication of 4 nucleotides in BRCA1 is denoted c.4335_4338dupAGAA at the cDNA level and p.Gln1447ArgfsX16 (Q1447RfsX16) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is ATCC[dupAGAA]CAAA. The duplication causes a frameshift, which changes a Glutamine to an Arginine at codon 1447, and creates a premature stop codon at position 16 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.4335_4338dupAGAA, previously reported as BRCA1 4454dup4, has been identified in several Korean breast/ovarian cancer patients (Kim 2012, Kang 2015). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000048527	SCV000591506	pathogenic	Hereditary breast ovarian cancer syndrome		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000048527	SCV000916760	pathogenic	Hereditary breast ovarian cancer syndrome	2018-06-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4335_4338dupAGAA (p.Gln1447ArgfsX16) 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 (e.g., p.Pro1464fsX2 and p.Ser1503X). The variant was absent in 246144 control chromosomes. c.4335_4338dupAGAA has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000167492	SCV001736418	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-17	criteria provided, single submitter	clinical testing	This variant inserts 4 nucleotides in exon 12 of the BRCA1 gene, creating a frameshift and premature translation stop signal. This variant is also known as 4454dupAGAA and c.4338_4339insAGAA in the literature. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple East Asian individuals affected with breast cancer (PMID: 22798144, 25863477, 28724667, 29673794, 30287823). 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.
Laboratory for Genotyping Development, RIKEN	RCV003162414	SCV002758307	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research