NM_000251.3:c.2779A>G

Variant names:

• chr2-47482923-A-G
• rs1553370905
• NM_000251.3:c.2779A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000251.3(MSH2):​c.2779A>G​(p.Ile927Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I927T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MSH2 NM_000251.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.94
• Publications: 0 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

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=0.17854166).
• BP6: Variant 2-47482923-A-G is Benign according to our data. Variant chr2-47482923-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2134355.

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.2779A>G	p.Ile927Val	missense	Exon 16 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406638.1		c.2818A>G	p.Ile940Val	missense	Exon 17 of 18	NP_001393567.1
	MSH2	NM_001406641.1		c.2779A>G	p.Ile927Val	missense	Exon 16 of 17	NP_001393570.1	P43246-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH2	ENST00000233146.7	TSL:1 MANE Select	c.2779A>G	p.Ile927Val	missense	Exon 16 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.2634+2052A>G		intron	N/A	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.2830A>G	p.Ile944Val	missense	Exon 17 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459638 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725974

African (AFR) AF: 0.00 AC: 0 AN: 33412

American (AMR) AF: 0.00 AC: 0 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00 AC: 0 AN: 85654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111284

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Hereditary nonpolyposis colorectal neoplasms (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.64	N
REVEL	Uncertain	0.46
Sift	Benign	0.17	T
Sift4G	Benign	0.19	T
Polyphen		0.0030	B
Vest4		0.15
MutPred		0.26		Loss of methylation at K931 (P = 0.0891)
MVP		0.95
MPC		0.0069
ClinPred		0.48	T
GERP RS		4.3
Varity_R		0.088
gMVP		0.15
Mutation Taster		=75/25	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: rs1553370905; hg19: chr2-47710062;