2-47410300-C-T

Variant names:

• chr2-47410300-C-T
• rs1800151
• NM_000251.3:c.573C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000251.3(MSH2):​c.573C>T​(p.Leu191Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00343 in 1,614,056 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L191L) has been classified as Likely benign. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.018 (88 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (92 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: 1.27
• Publications: 9 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 2-47410300-C-T is Benign according to our data. Variant chr2-47410300-C-T is described in ClinVar as Benign. ClinVar VariationId is 91140.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

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.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 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.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.573C>T	p.Leu191Leu	synonymous	Exon 3 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2757 AN: 152062 Hom.: 87 Cov.: 31

Gnomad AFR AF: 0.0639

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00475 AC: 1195 AN: 251458 AF XY: 0.00353

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00190 AC: 2783 AN: 1461876 Hom.: 92 Cov.: 32 AF XY: 0.00161 AC XY: 1171 AN XY: 727244

African (AFR) AF: 0.0712 AC: 2384 AN: 33480

American (AMR) AF: 0.00255 AC: 114 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1112004

Other (OTH) AF: 0.00391 AC: 236 AN: 60396

GnomAD4 genome AF: 0.0181 AC: 2761 AN: 152180 Hom.: 88 Cov.: 31 AF XY: 0.0177 AC XY: 1316 AN XY: 74398

African (AFR) AF: 0.0638 AC: 2647 AN: 41496

American (AMR) AF: 0.00550 AC: 84 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00553 Hom.: 18

Bravo AF: 0.0205

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	Lynch syndrome 1 (5)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	3	not provided (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Lynch syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	8.9
DANN	Benign	0.58
PhyloP100		1.3
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.030		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: rs1800151; hg19: chr2-47637439; COSMIC: COSV51876542;