5-80854162-A-C

Variant names:

• chr5-80854162-A-C
• rs184967
• NM_002439.5:c.2846A>C
• MSH3 p.Gln949Pro

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002439.5(MSH3):​c.2846A>C​(p.Gln949Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q949R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: MSH3 NM_002439.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

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>C	p.Gln949Pro	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>C	p.Gln949Pro	missense	Exon 21 of 24	ENSP00000265081.6	P20585
	MSH3	ENST00000658259.1		c.2678A>C	p.Gln893Pro	missense	Exon 21 of 24	ENSP00000499617.1	A0A590UJW0
	MSH3	ENST00000667069.1		c.2651A>C	p.Gln884Pro	missense	Exon 19 of 22	ENSP00000499502.1	A0A590UJN8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 45

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.43
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.044	D
Varity_R		0.83
gMVP		0.95
Mutation Taster		=84/16	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

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;