chr2-47482869-A-C

Position:

• chr2-47482869-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000251.3(MSH2):​c.2725A>C​(p.Lys909Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.68

Genes affected

MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2219617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2725A>C	p.Lys909Gln	missense_variant	16/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2725A>C	p.Lys909Gln	missense_variant	16/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MSH2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 05, 2022

The MSH2 c.2725A>C variant is predicted to result in the amino acid substitution p.Lys909Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/246423/?new_evidence=false). A different substitution affecting the same amino acid (p.Lys909Arg) has been reported in patients with colorectal cancer (Yurgelun et al. 2017. PubMed ID: 28135145 ). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 16, 2016

This variant is denoted MSH2 c.2725A>C at the cDNA level, p.Lys909Gln (K909Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys909Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Lys909Gln occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the helix-turn-helix domain (Lützen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Lys909Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246423). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 909 of the MSH2 protein (p.Lys909Gln). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.86	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	0.065	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.78	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.33	N;N
REVEL	Uncertain	0.42
Sift	Benign	0.26	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0010	B;.
Vest4		0.19
MutPred		0.37		Gain of ubiquitination at K907 (P = 0.0357);.;
MVP		0.85
MPC		0.0064
ClinPred		0.56	D
GERP RS		5.4
Varity_R		0.39
gMVP		0.24

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: rs879254253; hg19: chr2-47710008;