2-47410162-T-G

Variant names:

• chr2-47410162-T-G
• rs63750124
• NM_000251.3:c.435T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001406656.1(MSH2):​c.-561T>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000295 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: MSH2 NM_001406656.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:17
• Conservation: PhyloP100: -0.00500
• Publications: 31 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

Specifications for MSH2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1011188).
• BP6: Variant 2-47410162-T-G is Benign according to our data. Variant chr2-47410162-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 91097.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001406656.1. 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.435T>G	p.Ile145Met	missense	Exon 3 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406656.1		c.-561T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 17	NP_001393585.1
	MSH2	NM_001406658.1		c.-884T>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 16	NP_001393587.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.435T>G	p.Ile145Met	missense	Exon 3 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.435T>G	p.Ile145Met	missense	Exon 3 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.435T>G	p.Ile145Met	missense	Exon 3 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152168 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000322 AC: 81 AN: 251426 AF XY: 0.000353

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000290 AC: 424 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.000270 AC XY: 196 AN XY: 727226

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000320 AC: 356 AN: 1111976

Other (OTH) AF: 0.000397 AC: 24 AN: 60392

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152286 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74468

African (AFR) AF: 0.0000963 AC: 4 AN: 41556

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.000496 Hom.: 0

Bravo AF: 0.000408

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.00131

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	Hereditary cancer-predisposing syndrome (6)
-	1	4	not provided (5)
-	2	3	not specified (5)
-	2	1	Lynch syndrome 1 (3)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Breast carcinoma (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Colorectal cancer, non-polyposis (1)
-	-	1	Hereditary cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)
-	1	-	MSH2-related disorder (1)
-	1	-	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5399763:Mismatch repair cancer syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.0050
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.56
Sift	Benign	0.043	D
Sift4G	Benign	0.10	T
Polyphen		0.046	B
Vest4		0.81
MVP		1.0
MPC		0.011
ClinPred		0.0099	T
GERP RS		3.4
Varity_R		0.10
gMVP		0.59
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs63750124; hg19: chr2-47637301;