rs41295296

chr2-47480740-A-Cchr2-47480740-A-Gchr2-47480740-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000251.3(MSH2):c.2503A>C(p.Asn835His) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N835D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 4.40

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24905026).
• BP6: Variant 2-47480740-A-C is Benign according to our data. Variant chr2-47480740-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 90988.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=2, Benign=1}. Variant chr2-47480740-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MSH2	NM_000251.3	c.2503A>C	p.Asn835His	missense_variant	15/16	ENST00000233146.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MSH2	ENST00000233146.7	c.2503A>C	p.Asn835His	missense_variant	15/16	1	NM_000251.3	P1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251448 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1461816 Hom.: 0 Cov.: 32 AF XY: 0.000100 AC XY: 73 AN XY: 727206

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000187

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152202 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74356

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 13, 2023	Variant summary: MSH2 c.2503A>C (p.Asn835His) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, C-terminal domain (IPR000432) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251448 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2503A>C has been reported in the literature among individuals affected with endometrial cancer with uncertain MSI status (Hampel_2006), a colorectal cancer patient with MSI-low tumor, Tumor IHC positive for MLH1, MSH2, MSH6 (Barneston_2008), breast/ovarian cancer with negative BRCA testing (Maxwell_2014, South_2009, Jarhelle_2019, Bhai_2021, Li_2020), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18033691, 34326862, 16885385, 26951660, 31882575, 31391288, 25503501, 19117025). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=8, benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 28, 2016	The p.Asn835His variant in MSH2 has been reported in 2 individuals with Lynch sy ndrome-associated cancers (Hampel 2006, Barnetson 2008), where a lack of microsa tellite instability was observed in one of the individuals' colon tumor. This va riant has also been identified in 1/66684 of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41295296). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. Furthermore, this variant was cl assified as a variant of uncertain significance on Sept. 5, 2013 by the ClinGen- approved InSiGHT expert panel (ClinVar SCV000107519.2). In summary, the clinical significance of the p.Asn835His variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 22, 2020	DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2503A>C, in exon 15 that results in an amino acid change, p.Asn835His. This sequence change has been described in the gnomAD database with a low population frequency of 0.008% in the non-Finnish European subpopulation (dbSNP rs41295296). It has been previously described in patients with colorectal cancer, ovarian cancer, breast cancer and endometrial cancer (PMIDs: 19117025, 25503501, 16885385, 18033691). This variant was classified as benign based on its presence in one healthy control and lack of microsatellite instability in the colon tumor of one patient (PMID: 18033691). The p.Asn835His change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Asn835His substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asn835His change remains unknown at this time. -

Lynch syndrome 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 22, 2023	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	This missense variant replaces asparagine with histidine at codon 835 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers including colorectal (PMID: 18033691, 21671081), ovarian (PMID: 19117025), and endometrial cancer (PMID: 16885385). One individual with colorectal cancer showed high microsatellite instability and loss of MSH2 protein via immunohistochemistry (IHC) analysis, however, this individual also carried another MSH2 variant (PMID: 21671081). Another individual affected with colorectal cancer demonstrated low microsatellite instability and presence of MSH2 protein by IHC analysis (PMID: 18033691). The individual affected with endometrial cancer demonstrated intact MSH2 protein by IHC analysis, but did show loss of MLH1 protein and MLH1 methylation (PMID: 16885385). This variant has also been observed in two individuals affected with early onset breast cancer (PMID: 25503501, 31882575), an individual affected with breast and uterine cancer (PMID: 34326862), and in a large breast cancer case-control study it was observed in 17 affected and 7 unaffected individuals (PMID: 33471991). This variant has been identified in 10/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 25, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22949387, 31391288, 18033691, 16885385, 19117025, 26333163, 22290698, 25503501, 21671081, 17531815, 21153778, 30798936, 31882575) -

Lynch syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

This missense variant replaces asparagine with histidine at codon 835 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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). This variant has been reported in several individuals affected with Lynch syndrome-associated cancers including colorectal (PMID: 18033691, 21671081), ovarian (PMID: 19117025), and endometrial cancer (PMID: 16885385). One individual with colorectal cancer showed high microsatellite instability and loss of MSH2 protein via immunohistochemistry (IHC) analysis, however, this individual also carried another MSH2 variant (PMID: 21671081). Another individual affected with colorectal cancer demonstrated low microsatellite instability and presence of MSH2 protein by IHC analysis (PMID: 18033691). The individual affected with endometrial cancer demonstrated intact MSH2 protein by IHC analysis, but did show loss of MLH1 protein and MLH1 methylation (PMID: 16885385). This variant has also been observed in two individuals affected with early onset breast cancer (PMID: 25503501, 31882575), an individual affected with breast and uterine cancer (PMID: 34326862), and in a large breast cancer case-control study it was observed in 17 affected and 7 unaffected individuals (PMID: 33471991). This variant has been identified in 10/282854 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the available evidence indicates that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.40	T;.;.;.
Eigen	Benign	-0.18
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.18	N;.;.;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.43	N;N;.;N
REVEL	Benign	0.28
Sift	Benign	0.30	T;T;.;T
Sift4G	Benign	0.34	T;T;.;T
Polyphen		0.0010	B;.;.;B
Vest4		0.43
MVP		0.83
MPC		0.0064
ClinPred		0.13	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.20

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: rs41295296; hg19: chr2-47707879; COSMIC: COSV104575403;