chr2-47414405-T-G

Variant names:

• chr2-47414405-T-G
• rs63750640
• NM_000251.3:c.929T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PP3_Moderate PP1_Strong PM5 PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000251.3(MSH2):c.929T>G (p.Leu310Arg) variant is a missense variant replacing Leucin 310 to Arginin. The variant has been reported to co-segregate with disease in pedigree(s) with a combined* Bayes Likelihood Ratio >18.72 in ≥2 families (PMID:30376427, 33848333) (PP1_STR).The variant is a missense variant with MAPP+PolyPhen-2 prior probability for pathogenicity >0.81 as per http://priors.hci.utah.edu/PRIORS (PP3_MOD).The variant is a missense change at an amino acid residue where a different missense change was classified by this VCEP as Pathogenic on the protein level; p.Leu310Pro classified as Class 5 by InSiGHT (PM5).The variant has been detected in at least 2 independent CRC/Endometrial MSI-H tumours using a standard panel of 5-10 markersg and/or loss of MMR protein expression consistent with the variant location (PP4_MOD).The variant is not reported in gnomAD v4.1 (PM2_SUP). In summary, this variant meets the criteria to be classified as pathogenic for autosomal-dominant inherited Lynch-syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PM5, PP1_strong, PP4_moderate, PP3_moderate and PM2_supporting applied. (VCEP specifications version 1) LINK:https://erepo.genome.network/evrepo/ui/classification/CA022554/MONDO:0007356/137

• Frequency: Genomes: not found (cov: 26)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.97
• Publications: 10 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 11 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: 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.929T>G	p.Leu310Arg	missense	Exon 5 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.929T>G	p.Leu310Arg	missense	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.929T>G	p.Leu310Arg	missense	Exon 5 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.929T>G	p.Leu310Arg	missense	Exon 5 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.929T>G	p.Leu310Arg	missense	Exon 5 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.980T>G	p.Leu327Arg	missense	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 26

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		6.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.99
MPC		0.030
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs63750640; hg19: chr2-47641544; COSMIC: COSV51879724;