2-47475180-C-T

Variant names:

• chr2-47475180-C-T
• rs28929484
• NM_000251.3:c.1915C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000251.3(MSH2):​c.1915C>T​(p.His639Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,800 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 Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.40

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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a region_of_interest Interaction with EXO1 (size 70) in uniprot entity MSH2_HUMAN there are 24 pathogenic changes around while only 4 benign (86%) in NM_000251.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-47475180-C-T is Pathogenic according to our data. Variant chr2-47475180-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1756.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475180-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.1915C>T	p.His639Tyr	missense_variant	Exon 12 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.1915C>T	p.His639Tyr	missense_variant	Exon 12 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461800 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727208

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome 1 Pathogenic:2

Dec 17, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 04, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 8062247, 16395668]. -

Lynch syndrome Pathogenic:2

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Variant causes splicing aberration (full inactivation variant allele) -

Jan 08, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with tyrosine at codon 639 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). Splice site prediction tools indicate that this variant may activate a cryptic splice donor site 90 nucleotides upstream of the native intron 13 splice donor site. Functional RNA studies have shown that this cryptic splice donor site is used, leading to a deletion of 92 nucleotides in exon 12 (PMID: 8062247, 11920458, 16395668, 31588121, 32849802). As a result, this variant creates a frameshift and premature translation stop signal and is expected to result in an absent or non-functional protein product. 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). Other studies reported that the variant retained at least 58% of wild type MSH2 mismatch repair activity via mismatch repair assays in yeast (PMID: 11555625, 17720936). This variant has been reported in individuals affected with Lynch syndrome and colorectal cancer (PMID: 8062247, 8261515, 9718327, 11920458, 16395668, 24100870, 27329137, 31197828, 31588121). Some of these individuals also carried a pathogenic c.2211-1G>T in cis with this variant in MSH2 gene that could explain the observed phenotype (PMID: 9718327, 27329137). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Jan 12, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MSH2 c.1915C>T (p.His639Tyr) results in a conservative amino acid change located in the DNA mismatch repair protein Msh2, ATP-binding cassette domain (IPR032642) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5' donor site. One predicts the variant strengthens a cryptic 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (example: Auclair_2006). The variant was absent in 251510 control chromosomes (gnomAD). c.1915C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (example: Liu_1994, Leach_1993, Farrington_MSH2_AJHG_1998, Furukawa_2002, Auclair_2006, Terui_2013). At-least one of these reports have published a pathogenic variant in cis in one of the affected individuals (Farrington_1998). Multiple reports have published experimental evidence evaluating an impact on protein function. One of these studies showed the variant causes a defect in MMR function by in vivo drug-resistance assay in yeast; impair subunit interaction with Msh6 or Msh3, and reduce normal protein expression (example: Gammie_2007). The following publications have been ascertained in the context of this evaluation (PMID: 11555625, 9718327, 18383312, 8062247, 16395668, 14518068, 8261515, 9630599, 17720936, 17192056, 19339519, 22290698, 25559809, 11920458, 24100870). ClinVar contains an entry for this variant (Variation ID: 1756). Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Mar 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 639 of the MSH2 protein (p.His639Tyr). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 8062247, 8261515, 9718327, 11555625, 11920458, 16395668; Invitae). ClinVar contains an entry for this variant (Variation ID: 1756). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17720936). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 8062247, 16395668). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 09, 2019

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Result Def in combination with c.2211-1G>T: The c.1915C>T alteration (also known as p.H639Y), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1915. The histidine at codon 639 is replaced by tyrosine, an amino acid with similar properties. The c.2211-1G>T intronic alteration, results from a G to T one nucleotide upstream from coding exon 14 of the MSH2 gene. In one study, c.2211-1G>T was detected in cis with c.1915C>T, and this complex double mutation caused an in frame deletion of exons 12-14 in a patient diagnosed with colon cancer before 30 years of age. This result also correlated with short fragments detected by in vitro synthesized-protein&ndash;truncation assay. This individual's cancer was noted to exhibit microsatellite instability on tumor studies (Farrington et al. Am J Hum Genet. 1998 Sep; 63(3): 749-59). Based on the available evidence, the c.1915C>T+ c.2211-1G>T haplotype is interpreted as a disease-causing. Result Def when seen alone: The c.1915C>T pathogenic mutation (also known as p.H639Y), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1915. The histidine at codon 639 is replaced by tyrosine, an amino acid with similar properties. This variant has been identified in probands whose family histories met Amsterdam I/II criteria for Lynch syndrome and one was diagnosed with uterine cancer that demonstrated loss of both MSH2/MSH6 expression by immunohistochemistry (Ambry internal data). In one study, c.1915C>T was detected in a HNPCC kindred and it was predicted to create a novel donor splice site and to cause out of frame deletion of codons 638-669 creating a new termination codon 17 bp downstream of the splice site (Liu et al. Cancer Res. 1994 Sep 1; 54(17): 4590-4). mRNA analysis of this alteration confirmed aberrant splicing with deletion of 92 bases between 1914 and 2005 (r.1914_2005del) (Auclair et al. Hum Mut .2006 Feb; 27(2): 145-54). Yet in another study, c.1915C>T was detected in cis with another splicing mutation, c.2211-1G>T, and this double mutation caused deletion of exons 12-14 in a young patient diagnosed with colon cancer less than 30 years of age. This result also correlated with short fragments detected by in vitro synthesized-protein&ndash;truncation assay (Farrington et al. Am J Hum Genet. 1998 Sep; 63(3): 749-59). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.8	D;D;.;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.97
MutPred		0.99		Gain of catalytic residue at L634 (P = 0.0752);.;Gain of catalytic residue at L634 (P = 0.0752);Gain of catalytic residue at L634 (P = 0.0752);
MVP		0.98
MPC		0.033
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.99		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs28929484; hg19: chr2-47702319;