2-47403253-G-C

Variant names:

• chr2-47403253-G-C
• rs730881760
• NM_000251.3:c.62G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000251.3(MSH2):​c.62G>C​(p.Arg21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R21L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.58
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.62G>C	p.Arg21Pro	missense	Exon 1 of 16	NP_000242.1
	MSH2	NM_001406674.1		c.62G>C	p.Arg21Pro	missense	Exon 1 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.62G>C	p.Arg21Pro	missense	Exon 1 of 18	NP_001393560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.62G>C	p.Arg21Pro	missense	Exon 1 of 16	ENSP00000233146.2
	MSH2	ENST00000406134.5	TSL:1	c.62G>C	p.Arg21Pro	missense	Exon 1 of 16	ENSP00000384199.1
	MSH2	ENST00000645506.1		c.62G>C	p.Arg21Pro	missense	Exon 1 of 17	ENSP00000495455.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lynch syndrome 1 Uncertain:1

Nov 22, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.62G>C (p.Arg21Pro) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, however a functional study suggests that this missense change does not substantially impact MSH2 function (PMID: 33357406). To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Aug 01, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with MSH2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with proline at codon 21 of the MSH2 protein (p.Arg21Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.82
Sift	Benign	0.060	T
Sift4G	Benign	0.15	T
Polyphen		0.027	B
Vest4		0.68
MutPred		0.73		Gain of catalytic residue at M26 (P = 0.1044)
MVP		0.98
MPC		0.0060
ClinPred		0.98	D
GERP RS		4.6
PromoterAI		0.17	Neutral
Varity_R		0.97
gMVP		0.69
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs730881760; hg19: chr2-47630392;