7-6006029-G-C

Position:

• chr7-6006029-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000535.7(PMS2):​c.26C>G​(p.Thr9Arg) variant causes a missense, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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. T9A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PMS2 NM_000535.7 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.838

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS2	NM_000535.7	c.26C>G	p.Thr9Arg	missense_variant, splice_region_variant	2/15	ENST00000265849.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS2	ENST00000265849.12	c.26C>G	p.Thr9Arg	missense_variant, splice_region_variant	2/15	1	NM_000535.7	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.52	T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.26	T;T
Polyphen		0.0050	B;B
Vest4		0.26
MutPred		0.25		Gain of MoRF binding (P = 0.0082);Gain of MoRF binding (P = 0.0082);
MVP		0.85
MPC		0.076
ClinPred		0.19	T
GERP RS		1.7
Varity_R		0.055
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.68		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-6045660;