2-47416399-C-T

Variant names:

• chr2-47416399-C-T
• rs587779067
• NM_000251.3:c.1046C>T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1046C>T​(p.Pro349Leu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P349R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 7.76

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47416399-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-47416399-C-T is Pathogenic according to our data. Variant chr2-47416399-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 90514.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47416399-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.1046C>T	p.Pro349Leu	missense_variant	Exon 6 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1046C>T	p.Pro349Leu	missense_variant	Exon 6 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Jul 31, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 26951660]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21926548, 25117503]. -

Dec 05, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:1

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Multifactorial likelihood analysis posterior probability >0.99 -

not provided Pathogenic:1

Mar 08, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 349 of the MSH2 protein (p.Pro349Leu). 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: 15342696, 21926548, 25117503, 25420488). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MSH2 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MSH2 testing. ClinVar contains an entry for this variant (Variation ID: 90514). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MSH2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 26951660). This variant disrupts the p.Pro349 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21239990, 24278394, 26951660, 27606285). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Aug 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P349L pathogenic mutation (also known as c.1046C>T), located in coding exon 6 of the MSH2 gene, results from a C to T substitution at nucleotide position 1046. The proline at codon 349 is replaced by leucine, an amino acid with similar properties. This alteration was first reported in an individual diagnosed with multiple Lynch syndrome (LS)-associated cancers, from a family meeting Amsterdam II criteria, who tested negative for the BRAF-V600E mutation (Domingo E et al. J. Med. Genet. 2004 Sep;41:664-8). Further analysis of this family showed that this alteration segregated with family members affected with LS-associated cancers (Lindor NM et al. Pancreas. 2011 Oct;40:1138-40). This mutation also segregates with disease in two families tested by our laboratory (Ambry internal data). This mutation was more recently identified in a man diagnosed with prostate cancer at age 47, whose family met Amsterdam II criteria (Rosty C et al. Fam. Cancer. 2014 Dec;13:573-82) and has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species and is located in the highly conserved lever domain of the MSH2 protein that mediates signals between the ATP- and DNA-binding activities of MSH2. Studies of other alterations in this domain have been shown to negatively impact protein stability and showed loss of protein on tumor staining (Gammie AE et al. Genetics. 2007 Oct;177:707-21; Ollila S et al. Hum. Mutat. 2008 Nov;29:1355-63). 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	0.98
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.9	D;D;.;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.97
MutPred		0.96		Gain of MoRF binding (P = 0.0513);.;Gain of MoRF binding (P = 0.0513);Gain of MoRF binding (P = 0.0513);
MVP		0.99
MPC		0.035
ClinPred		1.0	D
GERP RS		5.6
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: rs587779067; hg19: chr2-47643538; COSMIC: COSV51876767;