chr2-47478312-G-C

Position:

• chr2-47478312-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.2251G>C​(p.Gly751Arg) variant causes a missense 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 9.33

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 Pathogenic. Variant got 18 ACMG points.

• PS1: Transcript NM_000251.3 (MSH2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-47478312-G-C is Pathogenic according to our data. Variant chr2-47478312-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 439192.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47478312-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MSH2	NM_000251.3	c.2251G>C	p.Gly751Arg	missense_variant	14/16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.2251G>C	p.Gly751Arg	missense_variant	14/16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 08, 2023	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726]. -
Likely pathogenic, reviewed by expert panel	curation	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Jun 13, 2018	Same amino acid change as pathogenic variant -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	This missense variant (c.2215G>T, p.Gly751Arg) replaces glycine with arginine at codon 751 in the MutL interaction 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 been reported in individuals affected with colorectal cancer with tumors showing microsatellite instability (PMID: 24278394, 26096739). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide change with the same protein consequence, c.2251G>A (p.Gly751Arg), is known to result in loss of MSH2 protein function and cause Lynch syndrome (ClinVar variation ID:90943). Based on the available evidence, this c.2215G>T (p.Gly751Arg) variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 30, 2022	The p.G751R pathogenic mutation (also known as c.2251G>C), located in coding exon 14 of the MSH2 gene, results from a G to C substitution at nucleotide position 2251. The glycine at codon 751 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been identified in multiple individuals with Lynch syndrome-related cancers, including families meeting Amsterdam criteria and individuals with tumor testing data highly suggestive of Lynch syndrome (Lucci-Cordisco E et al. Cancer Biomark. 2006;2(1-2):11-27; De Lellis L et al. PLoS ONE 2013 Nov;8(11):e81194; Duraturo F et al. Int. J. Mol. Med. 2015 Aug;36(2):511-7; Ambry internal data). Additionally, functional studies using a yeast-based assay have shown deficient protein function for p.G751R compared to wild-type (Gammie AE et al. Genetics. 2007 Oct;177(2):707-21). 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 deleterious (Jia X et al. Am J Hum Genet. 2021 01;108:163-175). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Feb 28, 2020

Not found in the total gnomAD dataset, and the data is high quality. Inconclusive segregation with disease. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936, 26951660, 31237724). 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. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 751 of the MSH2 protein (p.Gly751Arg). 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: 10530344, 10732761, 23990280, 25430799, 31118792, 31615790; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 439192). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.9	H;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.5	D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		1.0		Gain of phosphorylation at T754 (P = 0.1082);.;Gain of phosphorylation at T754 (P = 0.1082);Gain of phosphorylation at T754 (P = 0.1082);
MVP		0.99
MPC		0.033
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.99
gMVP		0.98

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: rs63751119; hg19: chr2-47705451; COSMIC: COSV105858552;