2-47410217-G-T

Variant names:

• chr2-47410217-G-T
• rs63750582
• NM_000251.3:c.490G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001406656.1(MSH2):​c.-506G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_001406656.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.92

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916
• PP5: Variant 2-47410217-G-T is Pathogenic according to our data. Variant chr2-47410217-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410217-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.490G>T	p.Gly164Trp	missense_variant	Exon 3 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.490G>T	p.Gly164Trp	missense_variant	Exon 3 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 26, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33357406, 26951660]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11208710, 26648449, Myriad internal data]. -

Familial colorectal cancer Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The MSH2 p.Gly164Trp variant was identified in 2 of 346 proband chromosomes (frequency: 0.006) from individuals or families with lynch syndrome (Terdiman 2001, Jansen 2016). The variant was identified in dbSNP (rs63750582) as 'Auwith pathogenic allele'Au and ClinVar (classified as uncertain significance by GeneDx and InSiGHT and pathogenic by Ambry Genetics). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified by our laboratory in two family members both with a MSH2-deficient colorectal tumour. In other laboratories, a pathogenic variant was observed at the same loci with a different protein change (p.Gly164Arg). In addition, the variant was also observed in an individual with MSH2/MSH6 deficient tumor and a second MSH2 somatic pathogenic variant was also identified (c.1511-1G>T, Jansen 2016). The p.Gly164 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2021

Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11208710, 18822302, 21120944, 26648449) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 25, 2023

This variant disrupts the p.Gly164 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1710317, 15849733, 18951462; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt MSH2 protein function. ClinVar contains an entry for this variant (Variation ID: 91110). This missense change has been observed in individuals with colorectal cancer (PMID: 11208710, 26648449; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the MSH2 protein (p.Gly164Trp). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The p.G164W pathogenic mutation (also known as c.490G>T), located in coding exon 3 of the MSH2 gene, results from a G to T substitution at nucleotide position 490. The glycine at codon 164 is replaced by tryptophan, an amino acid with highly dissimilar properties. This alteration was identified in individuals with early onset colorectal cancer that met Amsterdam I/II criteria for Lynch syndrome and/or had MSI-H tumors demonstrating loss of MSH2 on immunohistochemistry (IHC) (Ambry internal data; Jansen AM et al. Eur. J. Hum. Genet., 2016 07;24:1089-92; Terdiman JP et al. Gastroenterology, 2001 Jan;120:21-30). Another alteration at the same position, p.G164R, has been reported as a pathogenic mutation based on identification in individuals with Lynch syndrome and deficient function in an in vitro mismatch repair assay (Mangold et. al, Int J Cancer. 2005; 116(5): 692-702, Ou et al, Hum Mutat. 2007; 28(11): 1047-54, Lucci-Cordisco et. al., Cancer Biomarkers. 2006; 2:11-27; Ollila et al., Gastroent. 2006; 131: 1408). Based on an internal structural assessment, this alteration is in the core of the connector domain and is highly destabilizing in an established sensitive region (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-4.3	D;D;D;.;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0060	D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;.;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.90
MutPred		0.73		Loss of disorder (P = 0.0781);.;.;Loss of disorder (P = 0.0781);Loss of disorder (P = 0.0781);
MVP		0.97
MPC		0.033
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750582; hg19: chr2-47637356;