2-47475130-C-T

Variant names:

• chr2-47475130-C-T
• rs28929483
• NM_000251.3:c.1865C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000251.3(MSH2):​c.1865C>T​(p.Pro622Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P622R) has been classified as Likely 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:6
• Conservation: PhyloP100: 7.21

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-47475130-C-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-47475130-C-T is Pathogenic according to our data. Variant chr2-47475130-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1753.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47475130-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.1865C>T	p.Pro622Leu	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.1865C>T	p.Pro622Leu	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: 1461872 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727236

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:6

Revision: reviewed by expert panel

Submissions by phenotype

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

Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99 -

Nov 03, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The MSH2 c.1865C>T (p.Pro622Leu) variant involves the alteration of a conserved nucleotide located in the DNA mismatch repair protein MutS, core domain (IPR007696) (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). A yeast functional study showed 4% MMR activity associated with this variant (Gammie_2007). This variant is absent in 246248 control chromosomes in gnomAD. This variant was reported in multiple patients with LS and it showed perfect segregation with disease in affected families (Arnold_2009, Leach_1993). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Lynch syndrome 1 Pathogenic:1

Dec 17, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 28, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect: reduced protein expression, deficient ATP binding, abnormal cellular localization, and impaired MMR activity (Drotschmann et al., 1999; Fishel et al., 2000; Heinen et al., 2002; Belvederesi et al., 2008; Lutzen et al., 2008; Mastrocola et al., 2010; Rath et al., 2019; Jia et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16426447, 26951660, 11048710, 16804905, 21309037, 18383312, 31773066, 25117503, 17594722, 22949379, 22949387, 24362816, 19267393, 18822302, 9774676, 17426132, 22833534, 9630599, 22824075, 12385013, 22322191, 14518068, 12760035, 27035997, 8261515, 8062247, 16616355, 10469597, 22102614, 20672385, 12124176, 17192056, 11555625, 18781619, 17720936, 7717919, 28125613, 8484120, 31237724, 19072991, 33357406, 28422960, 28785832, 29967423, 19766128, 33119594, 31569399, 16116158, 21120944) -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Apr 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 622 of the MSH2 protein (p.Pro622Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 8261515, 16616355, 22283331, 25117503). It has also been observed to segregate with disease in related individuals. This variant is also known as 1933C>_x0001_T (P622L). ClinVar contains an entry for this variant (Variation ID: 1753). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 12124176, 17720936, 18822302, 19267393, 21309037, 22102614, 22949379, 24362816). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 04, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P622L pathogenic mutation (also known as c.1865C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1865. The proline at codon 622 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in numerous individuals meeting Amsterdam I/II criteria with absence of MSH2 and/or MSH6 on immunohistochemistry, and/or microsatellite unstable tumors (Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Schofield L et al. Int. J. Cancer 2009 Mar;124:1097-102; Arnold S et al. Hum. Mutat., 2009 May;30:757-70; Rosty C et al. Fam. Cancer 2014 Dec;13:573-82). Also, numerous studies in mammalian and yeast systems have demonstrated that this alteration results in reduced mismatch repair activity (Gammie AE et al. Genetics 2007 Oct;177:707-21; Lützen A et al. Mutat. Res. 2008 Oct;645:44-55; Mastrocola AS et al. Hum. Mutat. 2010 Oct;31:E1699-708; Wielders EA et al. Hum. Mutat. 2011 Apr;32:389-96; Drost M et al. Hum. Mutat. 2012 Mar;33:488-94; Houlleberghs H et al. Proc. Natl. Acad. Sci. U.S.A. 2016 Apr;113:4128-33). In the literature, this variant co-segregated with disease in 30 of 30 affected members in 2 families (Leach FS et al. Cell 1993 Dec;75:1215-25; Van de Water NS et al. Aust. N Z J Med. 1994 Dec;24:682-6; Jenkins MA et al. Int. J. Cancer 2002 Nov;102:166-71; Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98; Arnold S et al. Hum. Mutat. 2009 May;30:757-70). 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	0.89
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
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	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.9	H;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-9.6	D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;.;.;D
Vest4		0.99
MutPred		0.98		Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.99
MPC		0.035
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.95

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: rs28929483; hg19: chr2-47702269; COSMIC: COSV99253264; COSMIC: COSV99253264;