rs184967

Variant names:

• chr5-80854162-A-G
• rs184967
• NM_002439.5:c.2846A>G
• MSH3 p.Gln949Arg

Your query was ambiguous. Multiple possible variants found:

• chr5-80854162-A-G
• chr5-80854162-A-C
• chr5-80854162-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002439.5(MSH3):​c.2846A>G​(p.Gln949Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,612,888 control chromosomes in the GnomAD database, including 590,189 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q949W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.87 (57289 hom., cov: 30)
  • Exomes 𝑓: 0.85 (532900 hom.)
• Consequence: MSH3 NM_002439.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.429
• Publications: 76 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• MSH3-related attenuated familial adenomatous polyposis

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.7514077E-6).
• BP6: Variant 5-80854162-A-G is Benign according to our data. Variant chr5-80854162-A-G is described in ClinVar as Benign. ClinVar VariationId is 821892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	NM_002439.5	MANE Select	c.2846A>G	p.Gln949Arg	missense	Exon 21 of 24	NP_002430.3	P20585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MSH3	ENST00000265081.7	TSL:1 MANE Select	c.2846A>G	p.Gln949Arg	missense	Exon 21 of 24	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.2678A>G	p.Gln893Arg	missense	Exon 21 of 24	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.2651A>G	p.Gln884Arg	missense	Exon 19 of 22	ENSP00000499502.1	A0A590UJN8

Frequencies

GnomAD3 genomes AF: 0.867 AC: 131774 AN: 151978 Hom.: 57227 Cov.: 30

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.802

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.885

Gnomad FIN AF: 0.877

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.843

Gnomad OTH AF: 0.860

GnomAD2 exomes AF: 0.873 AC: 219003 AN: 250730 AF XY: 0.869

Gnomad AFR exome AF: 0.893

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.830

Gnomad EAS exome AF: 0.999

Gnomad FIN exome AF: 0.879

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.853 AC: 1246501 AN: 1460792 Hom.: 532900 Cov.: 45 AF XY: 0.853 AC XY: 619625 AN XY: 726778

African (AFR) AF: 0.888 AC: 29706 AN: 33462

American (AMR) AF: 0.907 AC: 40523 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 21530 AN: 26120

East Asian (EAS) AF: 1.00 AC: 39622 AN: 39636

South Asian (SAS) AF: 0.883 AC: 76167 AN: 86230

European-Finnish (FIN) AF: 0.875 AC: 46742 AN: 53410

Middle Eastern (MID) AF: 0.762 AC: 4389 AN: 5762

European-Non Finnish (NFE) AF: 0.843 AC: 936379 AN: 1111150

Other (OTH) AF: 0.852 AC: 51443 AN: 60346

GnomAD4 genome AF: 0.867 AC: 131897 AN: 152096 Hom.: 57289 Cov.: 30 AF XY: 0.869 AC XY: 64654 AN XY: 74358

African (AFR) AF: 0.892 AC: 37015 AN: 41496

American (AMR) AF: 0.867 AC: 13239 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.802 AC: 2779 AN: 3466

East Asian (EAS) AF: 0.999 AC: 5175 AN: 5182

South Asian (SAS) AF: 0.886 AC: 4262 AN: 4808

European-Finnish (FIN) AF: 0.877 AC: 9270 AN: 10576

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.843 AC: 57309 AN: 67984

Other (OTH) AF: 0.861 AC: 1816 AN: 2108

Alfa AF: 0.847 Hom.: 171786

Bravo AF: 0.868

Asia WGS AF: 0.932 AC: 3242 AN: 3478

EpiCase AF: 0.825

EpiControl AF: 0.831

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.3
DANN	Benign	0.86
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0000048	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.32	N
PhyloP100		0.43
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.58	N
REVEL	Benign	0.28
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R		0.080
gMVP		0.77
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs184967;

hg19: chr5-80149981;

COSMIC: COSV54143790;

COSMIC: COSV54143790;