2-47403203-G-T

Variant names:

• chr2-47403203-G-T
• rs878853800
• NM_000251.3:c.12G>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_000251.3(MSH2):​c.12G>T​(p.Gln4His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,250 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.23
• Publications: 1 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: G2P, ClinGen, Orphanet
• Lynch syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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: Labcorp Genetics (formerly Invitae), G2P
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37977555).
• BP6: Variant 2-47403203-G-T is Benign according to our data. Variant chr2-47403203-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 619517.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH2	NM_000251.3	c.12G>T	p.Gln4His	missense_variant	Exon 1 of 16	ENST00000233146.7	NP_000242.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH2	ENST00000233146.7	c.12G>T	p.Gln4His	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1445250 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717554

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33282

American (AMR) AF: 0.00 AC: 0 AN: 42024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25740

East Asian (EAS) AF: 0.00 AC: 0 AN: 39114

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83624

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105414

Other (OTH) AF: 0.00 AC: 0 AN: 59800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lynch syndrome Benign:1

May 01, 2018

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MSH2 NM_000251.2:c.12G>T has a 3.2% probability of pathogenicity based on combining prior probability from public data with likelihood ratios of 0.16 and 0.20 to 1, generated from evidence of seeing this as a somatic mutation in independent tumors with and without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	2.0	M;.;.
PhyloP100		1.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.9	N;.;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0080	D;.;D
Sift4G	Benign	0.23	T;.;T
Polyphen		0.12	B;.;D
Vest4		0.59
MutPred		0.24		Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);Loss of ubiquitination at K6 (P = 0.0547);
MVP		0.92
MPC		0.017
ClinPred		0.91	D
GERP RS		2.7
PromoterAI		-0.16	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.55
gMVP		0.55
Mutation Taster		=92/8	polymorphism

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: rs878853800; hg19: chr2-47630342;