Submissions for variant NM_007294.4(BRCA1):c.4484G>C (p.Arg1495Thr)

dbSNP: rs80357389

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000258262	SCV001161538	pathogenic	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 5 based on posterior probability = 0.993039
GeneDx	RCV000236135	SCV000292747	pathogenic	not provided	2015-10-29	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4484G>C at the cDNA level, p.Arg1495Thr (R1495T) at the protein level, and results in the change of an Arginine to a Threonine (AGG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 4603G>C. This variant was observed in an mRNA in-vitro splicing assay to create two aberrant transcripts, both of which lead to deleterious protein function, one skipping exon 14 and the other skipping exons 14-15 (Whiley 2014). BRCA1 Arg1495Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Arg1495Thr occurs at a position that is not conserved and is located within the SCD domain, the DNA binding domain and within a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available information, we consider BRCA1 Arg1495Thr to be a pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258262	SCV000325978	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580649	SCV000683188	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with threonine at codon 1495 of the BRCA1 protein and alters the conserved guanine nucleotide immediately adjacent to the intron 13 splice donor site. RNA study has shown that this variant causes the out-of-frame skipping of exon 13 and some in-frame skipping of exons 13 and 14 and does not produce full-length transcript (PMID: 24489791). This variant has been reported in at least three suspected hereditary breast and ovarian cancer families (PMID: 22762150, 27425403) and to have segregation and tumor pathology likelihood ratios for pathogenicity of 27.7342 and 9.99856, respectively (PMID: 31131967). Two similar variants at this nucleotide position, c.4484G>T and c.4484G>A, have been reported in individuals and families affected with breast and ovarian cancer (PMID: 10571952, 21120943, 24607278, 27741520, 28637432, 29339979) and shown by RNA analysis to cause out-of-frame skipping of exon 13 (PMID: 10571952, 12915465, 21120943, 22505045, 24607278, 31143303). 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.
Invitae	RCV001231407	SCV001403927	pathogenic	Hereditary breast ovarian cancer syndrome	2019-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with threonine at codon 1495 of the BRCA1 protein (p.Arg1495Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. It also falls at the last nucleotide of exon 13 of the BRCA1 coding sequence. For these reasons, this variant has been classified as Pathogenic. Experimental studies evaluating the effect of this sequence change on mRNA splicing have shown that this change results in aberrant splicing, leading to the skipping of exon 13 as well as exons 13-14 (PMID: 24489791, 22505045). In addition, a different variant affecting this nucleotide (c.4484G>T) segregates with disease (PMID: 24607278) and is classified as pathogenic (PMID: 24607278, 10571952, 12915465, 21120943), indicating that this nucleotide is important for normal RNA splicing. This variant has been reported in an individual affected with breast cancer (PMID: 24489791). ClinVar contains an entry for this variant (Variation ID: 245697). This variant is not present in population databases (ExAC no frequency).