Submissions for variant NM_007294.4(BRCA1):c.1106_1108del (p.Asp369del)

dbSNP: rs80358325

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000111551	SCV001161581	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 3.98E-07
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195341	SCV000075356	benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130879	SCV000185784	likely benign	Hereditary cancer-predisposing syndrome	2019-01-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001284384	SCV000209921	likely benign	not provided	2020-10-12	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 11044354, 19941162, 27153395, 8807330, 21990134, 17924331, 22753008, 20104584, 16267036, 16489001)
Counsyl	RCV000111551	SCV000220342	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2014-05-21	criteria provided, single submitter	literature only
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768648	SCV000324808	likely benign	Breast and/or ovarian cancer	2015-09-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130879	SCV000682936	likely benign	Hereditary cancer-predisposing syndrome	2015-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000047343	SCV000698832	benign	not specified	2020-07-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1106_1108delATG (p.Asp369del) results in an in-frame deletion that is predicted to remove an Asp amino acid from the encoded protein. The variant allele was found at a frequency of 5.3e-05 in 245906 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (5.3e-05 vs 0.001), allowing no conclusion about variant significance. c.1106_1108delATG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Chenevix-Trench_2006) that indicates the variant co-occurred in trans with a pathogenic BRCA1 variant, although the variant was not specified. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.4409_4410delTA, p.I470fsX11; BRCA2 c.7180A>T, p.Arg2394X), providing supporting evidence for a benign role. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer and co-segregation with disease in pedigrees (when available), predicted this variant to be neutral (Easton 2007, Lindor 2012). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. In addition, one expert panel classified this variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000111551	SCV001140611	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284384	SCV001470153	likely benign	not provided	2023-01-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130879	SCV002537995	likely benign	Hereditary cancer-predisposing syndrome	2021-06-26	criteria provided, single submitter	curation
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111551	SCV000144013	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-03-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000111551	SCV000591316	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing	The BRCA1 p.Asp369del variant is an in-frame deletion resulting in the removal of an aspartic acid (Asp) residue at codon 369. The variant was identified in at least 11 of 116044 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, and was not identified in 360 control chromosomes from healthy individuals (Borg 2010, Chenevix-Trench 2006 16489001, Couch 1996, Judkins 2005); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant is listed in dbSNP (ID: rs80358326) “With untested allele”; however, no frequency information was available for the variant. The variant was also identified in HGMD, LOVD, and the BIC database (2X with unknown clinical importance), and the ClinVar database (with one “uncertain significance” classification from BIC, and an unclassified submission from Invitae). Judkins (2005) identified this variant in trans with a known deleterious BRCA1 mutation (5385insC), increasing the likelihood that the p.Asp369del variant does not have clinical significance. A study by Chenevix-Trench (2006) demonstrated loss of the variant allele in tumours, suggesting that this variant is neutral. In addition, three multifactorial probability based models predict this to be a neutral variant (Chenevix-Trench 2006, Easton 2007, Lindor 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000782126	SCV000916303	likely benign	Ovarian cancer		no assertion criteria provided	clinical testing	The BRCA1 p.Asp369del variant is an in-frame deletion resulting in the removal of an aspartic acid (Asp) residue at codon 369. The variant was identified in at least 11 of 116044 proband chromosomes (frequency: 0.0001) from individuals or families with breast cancer, and was not identified in 360 control chromosomes from healthy individuals (Borg 2010, Chenevix-Trench 2006 16489001, Couch 1996, Judkins 2005); however, an insufficient number of controls were included in these studies to determine the frequency of this variant in the general population. The variant is listed in dbSNP (ID: rs80358326) ?With untested allele?; however, no frequency information was available for the variant. The variant was also identified in HGMD, LOVD, and the BIC database (2X with unknown clinical importance), and the ClinVar database (with one ?uncertain significance? classification from BIC, and an unclassified submission from Invitae). Judkins (2005) identified this variant in trans with a known deleterious BRCA1 mutation (5385insC), increasing the likelihood that the p.Asp369del variant does not have clinical significance. A study by Chenevix-Trench (2006) demonstrated loss of the variant allele in tumours, suggesting that this variant is neutral. In addition, three multifactorial probability based models predict this to be a neutral variant (Chenevix-Trench 2006, Easton 2007, Lindor 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004554646	SCV004719885	likely benign	BRCA1-related disorder	2019-06-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).