chr5-80656607-G-C

Variant names:

• chr5-80656607-G-C
• rs1650694
• NM_002439.5:c.358+76G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002439.5(MSH3):​c.358+76G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,586,528 control chromosomes in the GnomAD database, including 56,530 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.26 (5195 hom., cov: 32)
  • Exomes 𝑓: 0.26 (51335 hom.)
• Consequence: MSH3 NM_002439.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.76
• Publications: 10 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-80656607-G-C is Benign according to our data. Variant chr5-80656607-G-C is described in ClinVar as Benign. ClinVar VariationId is 1251884.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002439.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.358+76G>C		intron	N/A	NP_002430.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.358+76G>C		intron	N/A	ENSP00000265081.6
	MSH3	ENST00000658259.1		c.190+76G>C		intron	N/A	ENSP00000499617.1
	MSH3	ENST00000667069.1		c.358+76G>C		intron	N/A	ENSP00000499502.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39042 AN: 151954 Hom.: 5191 Cov.: 32

Gnomad AFR AF: 0.279

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.0475

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.286

GnomAD4 exome AF: 0.261 AC: 374507 AN: 1434456 Hom.: 51335 AF XY: 0.264 AC XY: 189072 AN XY: 714998

African (AFR) AF: 0.280 AC: 9176 AN: 32736

American (AMR) AF: 0.163 AC: 7141 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6928 AN: 25804

East Asian (EAS) AF: 0.0329 AC: 1297 AN: 39418

South Asian (SAS) AF: 0.325 AC: 27649 AN: 84952

European-Finnish (FIN) AF: 0.210 AC: 11004 AN: 52410

Middle Eastern (MID) AF: 0.425 AC: 2412 AN: 5680

European-Non Finnish (NFE) AF: 0.269 AC: 292966 AN: 1090206

Other (OTH) AF: 0.269 AC: 15934 AN: 59306

GnomAD4 genome AF: 0.257 AC: 39056 AN: 152072 Hom.: 5195 Cov.: 32 AF XY: 0.255 AC XY: 18924 AN XY: 74344

African (AFR) AF: 0.278 AC: 11547 AN: 41470

American (AMR) AF: 0.230 AC: 3511 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1026 AN: 3468

East Asian (EAS) AF: 0.0476 AC: 247 AN: 5186

South Asian (SAS) AF: 0.317 AC: 1530 AN: 4822

European-Finnish (FIN) AF: 0.205 AC: 2161 AN: 10566

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.266 AC: 18106 AN: 67976

Other (OTH) AF: 0.284 AC: 598 AN: 2102

Alfa AF: 0.101 Hom.: 81

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.56
DANN	Benign	0.40
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs1650694; hg19: chr5-79952426; COSMIC: COSV54144932;