rs1553351634

Variant names:

• chr2-47412492-A-C
• rs1553351634
• NM_000251.3:c.724A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47412492-A-C
• chr2-47412492-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000251.3(MSH2):​c.724A>C​(p.Asn242His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,736 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. N242K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 8.97
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.724A>C	p.Asn242His	missense_variant	Exon 4 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.724A>C	p.Asn242His	missense_variant	Exon 4 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459736 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726362

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110222

Other (OTH) AF: 0.00 AC: 0 AN: 60322

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Feb 08, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MSH2 c.724A>C (p.Asn242His) variant has not been reported in individuals with MSH2-related conditions in the published literature. In a large-scale breast cancer association study, the variant was only observed in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Dec 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18822302, 21120944) -

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 20, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces asparagine with histidine at codon 242 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 does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has not been identified 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. -

Aug 29, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N242H variant (also known as c.724A>C), located in coding exon 4 of the MSH2 gene, results from an A to C substitution at nucleotide position 724. The asparagine at codon 242 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary nonpolyposis colorectal neoplasms Uncertain:1

Sep 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 242 of the MSH2 protein (p.Asn242His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of MSH2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 485845). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 protein function. 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	Benign	0.27
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.8	M;.;.;.
PhyloP100		9.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.023	D;D;.;D
Sift4G	Uncertain	0.054	T;T;.;T
Polyphen		1.0	D;.;.;D
Vest4		0.86
MutPred		0.52		Loss of MoRF binding (P = 0.0991);.;Loss of MoRF binding (P = 0.0991);Loss of MoRF binding (P = 0.0991);
MVP		0.93
MPC		0.035
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.84
gMVP		0.52
Mutation Taster		=38/62	disease causing

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: rs1553351634; hg19: chr2-47639631;