2-47408449-C-G

Variant names:

• chr2-47408449-C-G
• rs587781447
• NM_000251.3:c.260C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000251.3(MSH2):​c.260C>G​(p.Ser87Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,611,528 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S87F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 5.11
• Publications: 8 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 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 22 benign, 43 uncertain in NM_000251.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• BP6: Variant 2-47408449-C-G is Benign according to our data. Variant chr2-47408449-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141032.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.260C>G	p.Ser87Cys	missense_variant	Exon 2 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.260C>G	p.Ser87Cys	missense_variant	Exon 2 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250910 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1460314 Hom.: 0 Cov.: 32 AF XY: 0.0000262 AC XY: 19 AN XY: 726470

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1110942

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151214 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73748

African (AFR) AF: 0.00 AC: 0 AN: 41058

American (AMR) AF: 0.00 AC: 0 AN: 15132

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67930

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lynch syndrome 1 Uncertain:2 Benign:1

Nov 14, 2023

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely 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: 27363726]. -

Mar 25, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 30, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Hereditary cancer-predisposing syndrome Uncertain:2

Sep 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (ClinGen VCEP defined LOF score threshold <=0, PMID: 33357406). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 chromosomes 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. -

Jul 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S87C variant (also known as c.260C>G), located in coding exon 2 of the MSH2 gene, results from a C to G substitution at nucleotide position 260. The serine at codon 87 is replaced by cysteine, an amino acid with dissimilar properties. This alteration was identified in a cohort of pancreatic cancer patients undergoing multigene panel testing (Young EL et al. BMC Cancer, 2018 Jun;18:697) and in a woman with primary peritoneal cancer who tested negative for the BRCA1 mutation previously identified in her family (Mitchell R et al. PLoS One, 2018 Apr;13:e0195497). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Lynch syndrome Uncertain:1

May 04, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with cysteine at codon 87 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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). This variant has been reported in individuals affected with breast, pancreatic or primary peritoneal cancers (PMID: 29659587, 29945567, 32547938). This variant has been identified in 2/282148 chromosomes 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. -

not provided Uncertain:1

Mar 06, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted MSH2 c.260C>G at the cDNA level, p.Ser87Cys (S87C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ser87Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH2 Ser87Cys is located in the mismatch binding domain (Lutzen 2008, Kansikas 2011). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MSH2 Ser87Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;D;.;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.9	M;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D;D;D;.;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0030	D;D;D;.;D
Sift4G	Uncertain	0.0080	D;D;D;.;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.67
MVP		0.84
MPC		0.0078
ClinPred		0.72	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.46
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587781447; hg19: chr2-47635588;