2-189805692-C-G

Variant names:

• chr2-189805692-C-G
• rs781542667
• NM_000534.5:c.356C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000534.5(PMS1):​c.356C>G​(p.Thr119Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

Genes affected

PMS1 (HGNC:9121): (PMS1 homolog 1, mismatch repair system component) This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3928251).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.356C>G	p.Thr119Ser	missense_variant	Exon 4 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.356C>G	p.Thr119Ser	missense_variant	Exon 4 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461492 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.356C>G (p.T119S) alteration is located in exon 4 (coding exon 3) of the PMS1 gene. This alteration results from a C to G substitution at nucleotide position 356, causing the threonine (T) at amino acid position 119 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T;T;T;T;T;.;T;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.39	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	1.0	.;.;.;L;.;L;.;.;L;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	.;.;.;N;N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.30	.;.;.;T;T;T;T;T;T;T
Sift4G	Benign	0.088	.;T;T;T;T;T;T;T;T;D
Polyphen		0.64, 0.15, 0.59	.;P;B;P;B;.;.;.;.;.
Vest4		0.56, 0.45, 0.50, 0.39, 0.56, 0.39, 0.49
MutPred		0.59		Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);Gain of disorder (P = 0.0665);.;
MVP		1.0
MPC		0.21
ClinPred		0.65	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs781542667; hg19: chr2-190670418;