ClinVar Miner

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

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Total submissions: 8
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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

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