2-47403295-G-T

Variant names:

• chr2-47403295-G-T
• rs1060502012
• NM_000251.3:c.104G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PP3_Moderate BP6_Moderate

The NM_000251.3(MSH2):​c.104G>T​(p.Arg35Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• 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: 9.15

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• BP6: Variant 2-47403295-G-T is Benign according to our data. Variant chr2-47403295-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1061189.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.104G>T	p.Arg35Leu	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.104G>T	p.Arg35Leu	missense_variant	Exon 1 of 16	1	NM_000251.3	ENSP00000233146.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000446 AC: 1 AN: 224044 Hom.: 0 AF XY: 0.00000820 AC XY: 1 AN XY: 121916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000319

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449836 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 720178

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary nonpolyposis colorectal neoplasms Benign:1

Aug 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Pathogenic	3.8	H;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.8	D;.;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.86
MutPred		0.65		Loss of catalytic residue at R35 (P = 0.0811);Loss of catalytic residue at R35 (P = 0.0811);Loss of catalytic residue at R35 (P = 0.0811);
MVP		0.96
MPC		0.031
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Varity_R		0.97
gMVP		0.85

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: rs1060502012; hg19: chr2-47630434;