2-47410346-G-T

Position:

• chr2-47410346-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The ENST00000233146.7(MSH2):​c.619G>T​(p.Ala207Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A207T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 ENST00000233146.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.03

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 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 17 uncertain in ENST00000233146.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.072766274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.619G>T	p.Ala207Ser	missense_variant	3/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.619G>T	p.Ala207Ser	missense_variant	3/16	1	NM_000251.3	ENSP00000233146	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727176

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MSH2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Apr 27, 2018

- -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 24, 2023

This missense variant replaces alanine with serine at codon 207 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been identified as a somatic variant in an individual affected with diffuse type advanced gastric adenocarcinoma that exhibited microsatellite instability (PMID: 9066723). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 28, 2021

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 MSH2 protein function. This variant has been reported in individual(s) in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 479819). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with serine at codon 207 of the MSH2 protein (p.Ala207Ser). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and serine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2019

The p.A207S variant (also known as c.619G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 619. The alanine at codon 207 is replaced by serine, an amino acid with similar properties. This alteration has been reported in the literature in a patient diagnosed with an MSI-high diffuse-type advanced gastric cancer at age 40 (Wu MS et al. Cancer Lett. 1997 Jan; 112(2):161-6). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	7.4
DANN	Benign	0.33
DEOGEN2	Benign	0.38	T;.;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.57	N;.;.;.
MutationTaster	Benign	0.58	D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.89	N;N;.;N
REVEL	Uncertain	0.45
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.0	B;.;.;B
Vest4		0.32
MutPred		0.35		Loss of catalytic residue at A207 (P = 0.0121);.;Loss of catalytic residue at A207 (P = 0.0121);Loss of catalytic residue at A207 (P = 0.0121);
MVP		0.91
MPC		0.0067
ClinPred		0.042	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.058
gMVP		0.29

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: rs63750913; hg19: chr2-47637485;