2-47466718-G-T

Position:

• chr2-47466718-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000251.3(MSH2):​c.1571G>T​(p.Arg524Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R524P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 9.06

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47466718-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1571G>T	p.Arg524Leu	missense_variant	10/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1571G>T	p.Arg524Leu	missense_variant	10/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727148

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2024	The p.R524L variant (also known as c.1571G>T), located in coding exon 10 of the MSH2 gene, results from a G to T substitution at nucleotide position 1571. The arginine at codon 524 is replaced by leucine, an amino acid with dissimilar properties. This variant was seen in a family from China that met Bethesda criteria and was not found in any of 100 matched control individuals (Sheng JQ et al. Cytogenet Genome Res. 2008;122(1):22-7). This variant was also seen in an individual with a colon tumor that was MSI-High and showed absent MSH2/MSH6 protein on IHC (Nyiraneza C et al. Hum Pathol. 2011 Dec;42(12):1897-910). However, this variant was also detected in an individual with a colon tumor with normal IHC staining that was MS-Stable (Ambry internal data). In a cell-free in vitro MMR activity assay, this variant was found to have proficient binding partner interaction and proficient nuclear localization (Drost M et al. Genet. Med., 2019 07;21:1486-1496). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 11, 2024	This missense variant replaces arginine with leucine at codon 524 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). This variant has intermediate MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold -1.32 < LOF score < 0.88, PMID: 33357406). In another functional study, this variant had a partial impact on mismatch repair activity in vitro, but exhibited proficient binding partner interaction and nuclear localization (PMID: 30504929). This variant has been reported in individuals affected with Lynch syndrome or Lynch syndrome-associated cancers (PMID: 18931482, 23640085, 32844218). One affected individual with colorectal cancer had a tumor exhibiting high microsatellite instability and loss of MSH2 and MSH6 protein via immunohistochemistry (PMID: 21665242). Another individual affected with endometrial cancer has a tumor that exibited loss of MSH2 and MSH6 protein as well (PMID: 32844218). However, it has been reported that an individual affected with colorectal cancer had a tumor exhibiting normal protein expression and was microsatellite stable (ClinVar: SCV000216488.6). A multifactorial likelihood analysis calculated the posterior probability of pathogenicity for this variant to be 0.681 (insight-database.org; PMID: 22949387). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1571G>C (p.Arg524Pro), is considered to be disease-causing (ClinVar variation ID: 1759), suggesting that this position is important for the protein function. Although there is a suspicion that this variant may be associated with disease, additional clinical and functional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Lynch syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 19, 2023

- -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2023

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 524 of the MSH2 protein (p.Arg524Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18931482, 31391288). ClinVar contains an entry for this variant (Variation ID: 90701). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MSH2 function (PMID: 30504929). This variant disrupts the p.Arg524 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7937795, 10469597, 15235030, 15849733, 17594722, 18931482, 20672385, 26845104). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.9	D;D;.;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.96
MutPred		0.73		Loss of MoRF binding (P = 0.0707);.;Loss of MoRF binding (P = 0.0707);Loss of MoRF binding (P = 0.0707);
MVP		0.99
MPC		0.032
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.81

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: rs63751207; hg19: chr2-47693857;