2-47783355-C-A

Position:

• chr2-47783355-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000234420.11(MSH6):​c.122C>A​(p.Ser41Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S41C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH6 ENST00000234420.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.578

Genes affected

MSH6 (HGNC:7329): (mutS homolog 6) This gene encodes a member of the DNA mismatch repair MutS family. In E. coli, the MutS protein helps in the recognition of mismatched nucleotides prior to their repair. A highly conserved region of approximately 150 aa, called the Walker-A adenine nucleotide binding motif, exists in MutS homologs. The encoded protein heterodimerizes with MSH2 to form a mismatch recognition complex that functions as a bidirectional molecular switch that exchanges ADP and ATP as DNA mismatches are bound and dissociated. Mutations in this gene may be associated with hereditary nonpolyposis colon cancer, colorectal cancer, and endometrial cancer. Transcripts variants encoding different isoforms have been described. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3655643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH6	NM_000179.3	c.122C>A	p.Ser41Tyr	missense_variant	1/10	ENST00000234420.11	NP_000170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH6	ENST00000234420.11	c.122C>A	p.Ser41Tyr	missense_variant	1/10	1	NM_000179.3	ENSP00000234420	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 02, 2015	The p.S41Y variant (also known as c.122C>A), located in coding exon 1 of the MSH6 gene, results from a C to A substitution at nucleotide position 122. The serine at codon 41 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5853 samples (11706 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 42000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. In addition, the CoDP in silico tool predicts this alteration to have minor impact on molecular function, with a score of 0.023 (Terui H et al. J. Biomed. Sci. 2013;20:25). Since supporting evidence is limited at this time, the clinical significance of p.S41Y remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 29, 2018	- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2022

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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 231150). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 41 of the MSH6 protein (p.Ser41Tyr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	0.99	D;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.053	T;T
Sift4G	Uncertain	0.018	D;T
Polyphen		0.94	.;P
Vest4		0.37
MutPred		0.20		Loss of glycosylation at S41 (P = 0.0057);Loss of glycosylation at S41 (P = 0.0057);
MVP		0.95
ClinPred		0.61	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.097
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs876658985; hg19: chr2-48010494;