chr2-47410245-T-C

Position:

chr2-47410245-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000251.3(MSH2):c.518T>C(p.Leu173Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L173R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MSH2
NM_000251.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.96

Variant links:

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]

MSH2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 14 uncertain in NM_000251.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-47410245-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 91122.Status of the report is reviewed_by_expert_panel, 3 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

PP5

Variant 2-47410245-T-C is Pathogenic according to our data. Variant chr2-47410245-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 91121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-47410245-T-C is described in Lovd as [Pathogenic]. Variant chr2-47410245-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3 linkuse as main transcript	c.518T>C	p.Leu173Pro	missense_variant	3/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7 linkuse as main transcript	c.518T>C	p.Leu173Pro	missense_variant	3/16	1	NM_000251.3	P1	P43246-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carcinoma of colon

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The p.Leu173Pro variant has been reported in the literature in 16/3584 proband chromosomes (Auclair 2006, Chao 2008, Kansikas 2011, Mangold 2005, Ollila 2006, Ollila 2006b, Ollila 2008, Ou 2007) from patients who met either the Bethesda criteria or Amsterdam criteria II. However, no control chromosomes were tested to establish the frequency of the variant in the general population. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs63750070), but no frequency information was provided, and so the prevalence of this variant in the population is not known. The p.Leu173 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Leu173Pro variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Functional assays evaluating the stability and/or MMR activity of the variant reveal that compared to the wildtype allele, the variant exhibits reduced repair efficiency and is also less stable (Ollila 2006b, Kansikas 2011, Ollila 2008). In addition, HNPCC-associated tumors from carriers were MSI-H and MSH2 deficient by immunohistochemistry (Kansikas 2011, Mangold 2005, Ollila 2006b). 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 Predicted Pathogenic. -

Hereditary nonpolyposis colon cancer

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

University of Washington Department of Laboratory Medicine, University of Washington

Oct 01, 2022

MSH2 NM_000251.2:c.518T>C has over 95% probability of pathogenicity based evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus and again as a germline variant paired with a single heterozygous somatic MSH2 mutation in a separate tumor. See Shirts et al 2018, PMID 29887214. -

Lynch syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces leucine with proline at codon 173 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes significantly decreased mismatch repair activity compared to wild type protein (PMID: 17101317, 17594722, 18951462), and that the variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). This variant has been reported in individuals affected with Lynch syndrome (PMID: 15849733, 17101317, 17594722, 18951462, 33422027). A different variant affecting the same codon, c.518T>G (p.Leu173Arg), is considered to be disease-causing (ClinVar variation ID: 91122), suggesting that this position is important for the protein function. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary nonpolyposis colorectal neoplasms

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 07, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu173 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011982, 22290698, 28577310, 28874130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462, 26951660). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 91121). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733, 16395668, 17101317, 18383312, 23741719; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 173 of the MSH2 protein (p.Leu173Pro). -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2020

The p.L173P variant (also known as c.518T>C), located in coding exon 3 of the MSH2 gene, results from a T to C substitution at nucleotide position 518. The leucine at codon 173 is replaced by proline, an amino acid with similar properties. This alteration was reported in an individual whose colorectal tumor demonstrated high microsatellite instabilty (MSI-H) with loss of MSH2 protein expression on immunohistochemistry (IHC) and had a family history that met Amsterdam criteria for Lynch syndrome (Mangold E et al. Int. J. Cancer, 2005 Sep;116:692-702; Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). This alteration was also identified as a somatic variant in conjunction with loss of heterozygosity of MSH2 in a Lynch syndrome-related tumor demonstrating MMR deficiency by IHC (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In an in vitro complementation assay using human nuclear extracts from a colorectal cell line, this alteration demonstrated reduced (less than 10%) mismatch repair (MMR) activity compared to wild type MSH2 (Ollila S et al. Gastroenterology, 2006 Nov;131:1408-17). In another functional study, this alteration showed resistance to a DNA damaging agent known to cause cell death in MMR-proficient cells, had reduced protein expression compared to wild type MSH2, and demonstrated microsatellite instability in a cellular assay using a slippage reporter (Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A., 2016 Apr;113:4128-33). Furthermore, this alteration demonstrated no aberrant splicing in a functional assay using RT-PCR (Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analysis (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D;.;.;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.99

D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Pathogenic

3.2

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.6

D;D;D;.;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D;D;.;D

Sift4G

Uncertain

0.0020

D;D;D;.;D

Polyphen

0.99

D;.;.;.;D

Vest4

0.92

MutPred

0.96

Loss of stability (P = 0.0308);.;.;Loss of stability (P = 0.0308);Loss of stability (P = 0.0308);

MVP

0.99

MPC

0.028

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.99

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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