Submissions for variant NM_007294.3(BRCA1):c.4083G>A (p.Met1361Ile) (rs374192364)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129891	SCV000184708	uncertain significance	Hereditary cancer-predisposing syndrome	2014-12-16	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx	RCV000766669	SCV000570599	uncertain significance	not provided	2016-06-08	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4083G>A at the cDNA level, p.Met1361Ile (M1361I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). Using alternate nomenclature, this variant would be defined as BRCA1 4202G>A. This variant has been observed in at least one individual with ovarian cancer (Alsop 2012). BRCA1 Met1361Ile was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met1361Ile occurs at a position that is not conserved and is located within the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Met1361Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000478992	SCV000591485	uncertain significance	not specified	2012-04-06	criteria provided, single submitter	clinical testing
Invitae	RCV000637459	SCV000758919	uncertain significance	Hereditary breast and ovarian cancer syndrome	2017-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with isoleucine at codon 1361 of the BRCA1 protein (p.Met1361Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs374192364, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37564). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Sharing Clinical Reports Project (SCRP)	RCV000031145	SCV000053745	uncertain significance	Breast-ovarian cancer, familial 1	2011-03-16	no assertion criteria provided	clinical testing