rs63751004

Variant names:

• chr2-47416365-G-A
• rs63751004
• NM_000251.3:c.1012G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-47416365-G-A
• chr2-47416365-G-C
• chr2-47416365-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP1 PM2_Supporting PS3 PP3_Moderate PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000251.3:c.1012G>A variant in MSH2 is a missense variant predicted to cause substitution of Glycine to Arginine at amino acid 338 (p.Gly338Arg). The prior probability for pathogenicity of this missense variant is 0.96 according to http://priors.hci.utah.edu/PRIORS (PP3_moderate). This variant has been identified in at least two independent patients with CRC: one tumor with loss of MSH2 and MSH6 protein expression and one tumour with loss of MSH2 protein expression (PP4_moderate). Results of functional and segregation odds support the evidence of pathogenicity of the variant (PS3 and PP1). This variant is absent from gnomAD v2.1.1 and gnomAD v4.1 (PM2_supporting).In summary, this variant meets the criteria to be classified as pathogenic for Lynch Syndrome, based on the MMR gene specific ACMG/AMP criteria established by the ClinGen InSiGHT Hereditary Colorectal Cancer/ Polyposis VCEP: PP3_Mod, PP4_Mod, PS3, PP1 and PM2_Sup (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA016843/MONDO:0005835/137

• Frequency: Genomes: not found (cov: 32)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 9.81
• Publications: 13 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: ClinGen, Orphanet, G2P
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 10 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000251.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	NM_000251.3	MANE Select	c.1012G>A	p.Gly338Arg	missense	Exon 6 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1012G>A	p.Gly338Arg	missense	Exon 6 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1012G>A	p.Gly338Arg	missense	Exon 6 of 18	NP_001393560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.1012G>A	p.Gly338Arg	missense	Exon 6 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1012G>A	p.Gly338Arg	missense	Exon 6 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1063G>A	p.Gly355Arg	missense	Exon 7 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Lynch syndrome 1 (2)
-	1	-	Carcinoma of colon (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.96		Gain of MoRF binding (P = 0.0256)
MVP		0.99
MPC		0.033
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.99
gMVP		0.89
Mutation Taster		=1/99	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: rs63751004; hg19: chr2-47643504; COSMIC: COSV99253467;