rs61756466

Variant names:

• chr2-47470969-T-C
• rs61756466
• NM_000251.3:c.1666T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-47470969-T-C
• chr2-47470969-T-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000251.3(MSH2):​c.1666T>C​(p.Leu556Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,469,858 control chromosomes in the GnomAD database, including 38 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. L556L) has been classified as Benign. The gene MSH2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0046 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (36 hom.)
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Benign reviewed by expert panel B:30
• Conservation: PhyloP100: 1.07
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-47470969-T-C is Benign according to our data. Variant chr2-47470969-T-C is described in ClinVar as Benign. ClinVar VariationId is 36568.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP7: Synonymous conserved (PhyloP=1.08 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00456 (694/152302) while in subpopulation NFE AF = 0.00651 (443/68018). AF 95% confidence interval is 0.00601. There are 2 homozygotes in GnomAd4. There are 330 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

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.1666T>C	p.Leu556Leu	synonymous	Exon 11 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.1666T>C	p.Leu556Leu	synonymous	Exon 11 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.1666T>C	p.Leu556Leu	synonymous	Exon 11 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.1666T>C	p.Leu556Leu	synonymous	Exon 11 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.1666T>C	p.Leu556Leu	synonymous	Exon 11 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.1717T>C	p.Leu573Leu	synonymous	Exon 12 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152184 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00651

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00428 AC: 1071 AN: 249980 AF XY: 0.00445

Gnomad AFR exome AF: 0.00156

Gnomad AMR exome AF: 0.00227

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00525

GnomAD4 exome AF: 0.00544 AC: 7168 AN: 1317556 Hom.: 36 Cov.: 20 AF XY: 0.00535 AC XY: 3546 AN XY: 663382

African (AFR) AF: 0.000848 AC: 26 AN: 30656

American (AMR) AF: 0.00223 AC: 99 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00345 AC: 87 AN: 25232

East Asian (EAS) AF: 0.00 AC: 0 AN: 38884

South Asian (SAS) AF: 0.00111 AC: 92 AN: 82900

European-Finnish (FIN) AF: 0.00415 AC: 221 AN: 53254

Middle Eastern (MID) AF: 0.00506 AC: 26 AN: 5136

European-Non Finnish (NFE) AF: 0.00644 AC: 6321 AN: 981700

Other (OTH) AF: 0.00535 AC: 296 AN: 55316

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152302 Hom.: 2 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74474

African (AFR) AF: 0.00171 AC: 71 AN: 41570

American (AMR) AF: 0.00523 AC: 80 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00651 AC: 443 AN: 68018

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00555 Hom.: 1

Bravo AF: 0.00433

EpiCase AF: 0.00742

EpiControl AF: 0.00694

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	6	Lynch syndrome 1 (6)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	3	not provided (3)
-	-	2	Lynch syndrome (2)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	Carcinoma of colon (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Muir-Torré syndrome;C2936783:Lynch syndrome 1;C5436806:Mismatch repair cancer syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.3
DANN	Benign	0.69
PhyloP100		1.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs61756466; hg19: chr2-47698108;