Submissions for variant NM_007294.4(BRCA1):c.4060AAT[1] (p.Asn1355del)

dbSNP: rs80358341

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132449	SCV000187543	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-23	criteria provided, single submitter	clinical testing	The c.4063_4065delAAT variant (also known as p.N1355del) is located in coding exon 9 of the BRCA1 gene. This variant results from an in-frame AAT deletion at nucleotide positions 4063 to 4065. This results in the in-frame deletion of an asparagine at codon 1355. This alteration was identified in multiple individuals diagnosed with breast and/or ovarian cancer (Konstantopoulou I et al. Breast Cancer Res Treat. 2008 Feb;107(3):431-41; Lara K et al. Biol Res. 2012;45(2):117-30; Loizidou MA et al. Clin. Genet. 2017 Apr;91:611-615; Fanale D et al. Front Oncol, 2021 Jun;11:682445). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000168505	SCV000219237	uncertain significance	Breast and/or ovarian cancer	2015-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000758822	SCV000293645	uncertain significance	not provided	2019-11-13	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with personal or family history of breast and ovarian cancer (Konstantopoulou 2008, Loizidou 2017); Observed with a pathogenic BRCA1 variant, phase unknown, in unrelated individuals referred for genetic testing at GeneDx and in published literature (Lara 2012); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Located in a critical functional domain: SCD domain (Narod 2004, Clark 2012); Also known as 4182_4184delAAT; This variant is associated with the following publications: (PMID: 27882536, 17453335, 31658756, 28726806, 23096355)
Counsyl	RCV000112237	SCV000785153	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758822	SCV000887684	uncertain significance	not provided	2024-07-29	criteria provided, single submitter	clinical testing	The BRCA1 c.4063_4065del (p.Asn1355del) variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer, including an individual with early onset breast cancer carrying a second pathogenic BRCA1 variant (PMID: 38741424 (2024), 34178674 (2021), 31954625 (2020), 27882536 (2016), 23096355 (2012), 17453335 (2008)). The frequency of this variant in the general population, 0.000004 (1/250834 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000132449	SCV000903321	likely benign	Hereditary cancer-predisposing syndrome	2016-12-09	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001068437	SCV001233549	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-15	criteria provided, single submitter	clinical testing	This variant, c.4063_4065del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.Asn1355del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs80358341, gnomAD 0.0009%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 17453335, 23096355, 27882536, 31954625, 34178674; internal data). This variant has been observed to co-occur in individuals with a different variant in BRCA1 that has been determined to be pathogenic (internal data), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 55093). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV004803993	SCV004817712	likely benign	BRCA1-related cancer predisposition	2024-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700338	SCV005203035	uncertain significance	not specified	2024-07-22	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4063_4065delAAT (p.Asn1355del) results in an in-frame deletion that is predicted to remove 1 amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250834 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4063_4065delAAT has been reported in the literature in the presumed heterozygous state in multiple individuals affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Bisgin_2022, Boga_2023, Eras_2024, Fanale_2021, Incorvaia_2020, Lara_2012, Loizidou_2017, Solmaz_2020, Urbina-Jara_2021). These report(s) do not provide unequivocal conclusions about association of the variant with BRCA1-related conditions. Co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA1 c.1016_1017insA, p.Lys339fs?), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35753294, 37415649, 38741424, 34178674, 32380732, 23096355, 27882536, 31954625, 34884835). ClinVar contains an entry for this variant (Variation ID: 55093). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112237	SCV000144951	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing