Submissions for variant NM_007294.4(BRCA1):c.4060AAT[1] (p.Asn1355del) (rs80358341)

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132449	SCV000187543	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-03	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 deletion of 3 nucleotides at positions 4063 to 4065. This results in the deletion of an asparagine residue at codon 1355. This alteration was identified in 1 of 527 index patients with either breast, ovarian, or pancreatic cancer in Cyprus (Loizidou MA et al. Clin. Genet. 2017 Apr;91:611-615), as well as in 2 of 58 breast cancer patients from Venezuela, both with a family history of breast and ovarian cancer (Lara K et al. Biol Res. 2012;45(2):117-30). In addition, this variant was reported in 1 of 127 Greek breast and/or ovarian cancer families (Konstantopoulou I et al. Breast Cancer Res Treat. 2008 Feb;107(3):431-41). However, in all of these studies, this variant was classified as unknown significance. Based on protein sequence alignment, 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	2018-08-21	criteria provided, single submitter	clinical testing	This in-frame deletion of three nucleotides in BRCA1 is denoted c.4063_4065delAAT at the cDNA level and p.Asn1355del (N1355del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 c.4182_4184delAAT. The normal sequence, with the bases that are deleted in brackets, is AAAT[delAAT]CAAG. This variant was observed in at least three breast and/or ovarian cancer families, one of which also carried a pathogenic BRCA1 frameshift variant, phase unknown (Lara 2012, Konstantopoulou 2008, Loizidou 2017). BRCA1 c.4063_4065delAAT was not observed at a significant allele frequency in large population cohorts (Lek 2016). This deletion of a single Asparagine amino acid is located in a region known to interact with multiple proteins (Paul 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 Asn1355del to be a variant of uncertain significance.
Counsyl	RCV000112237	SCV000785153	uncertain significance	Breast-ovarian cancer, familial 1	2017-05-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758822	SCV000887684	uncertain significance	not provided	2017-11-24	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000132449	SCV000903321	likely benign	Hereditary cancer-predisposing syndrome	2016-12-09	criteria provided, single submitter	clinical testing
Invitae	RCV001068437	SCV001233549	uncertain significance	Hereditary breast and ovarian cancer syndrome	2020-08-20	criteria provided, single submitter	clinical testing	This variant, c.4063_4065delAAT, results in the deletion of 1 amino acid of the BRCA1 protein (p.Asn1355del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 17453335, 23096355, 27882536, Invitae). However, in one of these individuals pathogenic allele[s] were also identified in BRCA1, which suggests that this c.4063_4065del variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 55093). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112237	SCV000144951	uncertain significance	Breast-ovarian cancer, familial 1	2002-05-29	no assertion criteria provided	clinical testing