NM_000251.3:c.939T>C

Variant names:

• chr2-47414415-T-C
• rs970103452
• NM_000251.3:c.939T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000251.3(MSH2):​c.939T>C​(p.Phe313Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH2 NM_000251.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.256
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-47414415-T-C is Benign according to our data. Variant chr2-47414415-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 525943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.256 with no splicing effect.

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.939T>C	p.Phe313Phe	synonymous	Exon 5 of 16	NP_000242.1	P43246-1
	MSH2	NM_001406674.1		c.939T>C	p.Phe313Phe	synonymous	Exon 5 of 18	NP_001393603.1
	MSH2	NM_001406631.1		c.939T>C	p.Phe313Phe	synonymous	Exon 5 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.939T>C	p.Phe313Phe	synonymous	Exon 5 of 16	ENSP00000233146.2	P43246-1
	MSH2	ENST00000406134.5	TSL:1	c.939T>C	p.Phe313Phe	synonymous	Exon 5 of 16	ENSP00000384199.1	E9PHA6
	MSH2	ENST00000918107.1		c.990T>C	p.Phe330Phe	synonymous	Exon 6 of 17	ENSP00000588166.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 116892 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1401440 Hom.: 0 Cov.: 43 AF XY: 0.00 AC XY: 0 AN XY: 696856

African (AFR) AF: 0.00 AC: 0 AN: 30158

American (AMR) AF: 0.00 AC: 0 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24386

East Asian (EAS) AF: 0.00 AC: 0 AN: 38744

South Asian (SAS) AF: 0.00 AC: 0 AN: 77542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084988

Other (OTH) AF: 0.00 AC: 0 AN: 57334

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 116892 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 55956

African (AFR) AF: 0.00 AC: 0 AN: 29672

American (AMR) AF: 0.00 AC: 0 AN: 10830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4340

South Asian (SAS) AF: 0.00 AC: 0 AN: 3126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6724

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 56762

Other (OTH) AF: 0.00 AC: 0 AN: 1386

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.2
DANN	Benign	0.71
PhyloP100		0.26
Mutation Taster		=88/12	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: rs970103452; hg19: chr2-47641554;