rs63750790

Positions:

• chr2-47476425-G-A
• chr2-47476425-G-C
• chr2-47476425-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_000251.3(MSH2):​c.2064G>A​(p.Met688Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M688R) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000041 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:14 B:1
• Conservation: PhyloP100: 9.60

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 5 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 12 uncertain in NM_000251.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47476424-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 90874.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2064G>A	p.Met688Ile	missense_variant	13/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2064G>A	p.Met688Ile	missense_variant	13/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251466 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000410 AC: 60 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000275 AC XY: 20 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00149

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000513 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:14 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Uncertain:6

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 29, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: mixed results with respect to mismatch repair activity, protein stability, and binding ability (Gammie et al., 2007; Wielders et al., 2011; Martin-Lopez et al., 2012; Houlleberghs et al., 2016; Jia et al., 2020); Observed in individuals with colon cancer, gastric cancer, pancreatic, and other cancers, or hereditary non-polyposis colorectal cancer (HNPCC), as well as in healthy controls (Yuan et al., 1998; Nomura et al., 2000; Banno et al., 2004; Kim et al., 2017; Terashima et al., 2022; Scott et al., 2022; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 24933000, 22039344, 29050249, 22949387, 31386297, 22739024, 17720936, 21309037, 9559627, 26951660, 23760103, 26332594, 15365995, 10777691, 23741719, 15527911, 25871441, 30093976, 31396961, 32566746, 33357406, 34570441, 34328007, 26206375, 22179786, 15075785, 14499697, 36135357, 18822302, 21120944, 36550560, 37559881, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2022	The frequency of this variant in the general population, 0.0021 (8/3814 chromosomes in Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with polyps (PMID: 9559627 (1998)), colon cancer (PMID: 10777691 (2000), 23741719 (2013)), endometrial cancer (PMID: 14499697 (2003)), gastric cancer (PMID: 29050249 (2017)), breast cancer (PMID: 30093976 (2018), 33471991 (2021), 34570441 (2021)), and an unspecified cancer (PMID: 31386297 (2019)). Some of these individuals were suspected of hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 9559627 (1998), 10777691 (2000), 14499697 (2003)), and Lynch Syndrome (PMID: 31386297 (2019)). However, this variant has also been reported in unaffected individuals (PMID: 15527911 (2004), 26332594 (2015), 33471991 (2021)). Functional studies of this variant on the effect of MSH2 protein function were inconclusive ((PMID: 17720936 (2007), 21309037 (2011), 22739024 (2012), 26951660 (2016), 33357406 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2022	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 09, 2023	This missense variant replaces methionine with isoleucine at codon 688 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated normal to intermediate impact in mismatch repair assays (PMID: 17720936, 21309037, 22739024, 26951660, 33357406) and normal interaction with MSH2, MSH6, and MLH1 (PMID: 21309037). This variant has been reported in individuals affected with colorectal, endometrial cancer (PMID: 9559627, 10777691, 14499697, 15365995), gastric cancer (PMID: 29050249), and esophageal cancer (PMID: 31396961) in the literature, but also in healthy individuals (PMID: 15527911). This variant has been identified in 8/251466 chromosomes 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 01, 2024

Variant summary: MSH2 c.2064G>A (p.Met688Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 252024 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00057), allowing no conclusion about variant significance. c.2064G>A has been reported in the literature in multiple individuals/families affected with suspected Lynch Syndrome (examples- Yuan_1998, Nomura_2000, Banno_2003, Shin_2004), but has also been reported in unaffected controls (examples- Banno_2004, Olfson_2015). Two large case-control studies evaluating breast cancer genetic risk also reported this variant was not significantly enriched in the case cohorts (Dorling_2021, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (BRCA2 c.1813delA, p.Ile605Tyrfs), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in an intermediate mismatch-repair phenotype in a yeast-based assay (Gammie_2007), however most subsequent reports indicate no overall damaging effects of the variant on mismatch repair function and ability to interact with its binding partner MSH6 (examples- Wielders_2010, Martin-Lopez_2012, Houlleberghs_2016, Jia_2021). The following publications have been ascertained in the context of this evaluation (PMID: 14499697, 15527911, 30093976, 33471991, 17720936, 26951660, 33357406, 29050249, 31386297, 22739024, 10777691, 36243179, 26332594, 15365995, 21309037, 9559627, 23760103). ClinVar contains an entry for this variant (Variation ID: 90875). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces methionine with isoleucine at codon 688 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have demonstrated normal to intermediate impact in mismatch repair assays (PMID: 17720936, 21309037, 22739024, 26951660, 33357406) and normal interaction with MSH2, MSH6, and MLH1 (PMID: 21309037). This variant has been reported in individuals affected with colorectal, endometrial cancer (PMID: 9559627, 10777691, 14499697, 15365995), gastric cancer (PMID: 29050249), and esophageal cancer (PMID: 31396961) in the literature, but also in healthy individuals (PMID: 15527911). This variant has been identified in 8/251466 chromosomes 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

Invitae

Dec 06, 2023

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 688 of the MSH2 protein (p.Met688Ile). This variant is present in population databases (rs63750790, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9559627, 10777691, 14499697, 23741719, 30093976, 31386297, 31396961, 36135357). ClinVar contains an entry for this variant (Variation ID: 90875). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MSH2 function (PMID: 17720936, 21309037, 22739024, 33357406). This variant disrupts the p.Met688 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10080150, 15075785, 20010080, 21225464, 21239990, 22739024). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Pathogenic	3.5	H;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D;.;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.93
MutPred		0.96		Gain of loop (P = 0.3485);.;Gain of loop (P = 0.3485);Gain of loop (P = 0.3485);
MVP		0.98
MPC		0.030
ClinPred		0.93	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.96

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: rs63750790; hg19: chr2-47703564; COSMIC: COSV51886508; COSMIC: COSV51886508;