chr5-80655314-T-G

Variant names:

• chr5-80655314-T-G
• rs408626
• NM_002439.5:c.237+350T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002439.5(MSH3):​c.237+350T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.253
• Publications: 0 publications found

Genes affected

MSH3 (HGNC:7326): (mutS homolog 3) The protein encoded by this gene forms a heterodimer with MSH2 to form MutS beta, part of the post-replicative DNA mismatch repair system. MutS beta initiates mismatch repair by binding to a mismatch and then forming a complex with MutL alpha heterodimer. This gene contains a polymorphic 9 bp tandem repeat sequence in the first exon. The repeat is present 6 times in the reference genome sequence and 3-7 repeats have been reported. Defects in this gene are a cause of susceptibility to endometrial cancer. [provided by RefSeq, Mar 2011]

MSH3 Gene-Disease associations (from GenCC):

• familial adenomatous polyposis 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• MSH3-related attenuated familial adenomatous polyposis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Lynch syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MSH3	NM_002439.5	c.237+350T>G		intron_variant	Intron 1 of 23	ENST00000265081.7	NP_002430.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MSH3	ENST00000265081.7	c.237+350T>G		intron_variant	Intron 1 of 23	1	NM_002439.5	ENSP00000265081.6
MSH3	ENST00000658259.1	c.69+52T>G		intron_variant	Intron 1 of 23			ENSP00000499617.1
MSH3	ENST00000667069.1	c.237+350T>G		intron_variant	Intron 1 of 21			ENSP00000499502.1
MSH3	ENST00000670357.1	n.237+350T>G		intron_variant	Intron 1 of 24			ENSP00000499791.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 94408 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 44284

African (AFR) AF: 0.00 AC: 0 AN: 4370

American (AMR) AF: 0.00 AC: 0 AN: 2838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5514

East Asian (EAS) AF: 0.00 AC: 0 AN: 11576

South Asian (SAS) AF: 0.00 AC: 0 AN: 1312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 548

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 59698

Other (OTH) AF: 0.00 AC: 0 AN: 7626

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.6
DANN	Benign	0.66
PhyloP100		0.25
PromoterAI		-0.0024	Neutral

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: rs408626; hg19: chr5-79951133;