Submissions for variant NM_000179.3(MSH6):c.3610G>A (p.Ala1204Thr)

dbSNP: rs869312799

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210134	SCV000266210	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000663332	SCV000786606	uncertain significance	Lynch syndrome 5	2018-06-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001020725	SCV001182238	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-01	criteria provided, single submitter	clinical testing	The p.A1204T variant (also known as c.3610G>A), located in coding exon 7 of the MSH6 gene, results from a G to A substitution at nucleotide position 3610. The alanine at codon 1204 is replaced by threonine, an amino acid with similar properties. This alteration was detected in an individual with fallopian tube cancer that had intact staining for the mismatch repair genes by immunohistochemistry (IHC) (Shirts BH et al. Genet Med, 2016 10;18:974-81). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001358963	SCV001554820	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1204 of the MSH6 protein (p.Ala1204Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26845104). ClinVar contains an entry for this variant (Variation ID: 224583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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.
GeneDx	RCV003231405	SCV003929860	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with fallopian tube cancer whose tumor displayed normal mismatch repair immunohistochemistry (Shirts et al., 2016); This variant is associated with the following publications: (PMID: 30761385, 17531815, 21120944, 26845104)
Myriad Genetics, Inc.	RCV000663332	SCV004018850	uncertain significance	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.