2-189795811-G-C

Variant names:

• chr2-189795811-G-C
• NM_000534.5:c.175G>C

Variant summary

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

The NM_000534.5(PMS1):​c.175G>C​(p.Glu59Gln) 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 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07

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=0.29133973).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.175G>C	p.Glu59Gln	missense_variant	Exon 3 of 13	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.175G>C	p.Glu59Gln	missense_variant	Exon 3 of 13	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461616 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.23	T;T;T;T;T;.;T;T;.;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T;T;T;D;D;T;D;T;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.57	.;.;.;N;.;N;.;.;N;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.28	.;.;.;N;N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.32	.;.;.;T;T;T;T;T;T;T
Sift4G	Benign	0.56	.;T;T;T;T;T;T;T;T;T
Polyphen		0.034, 0.0020, 0.061	.;B;B;B;B;.;.;.;.;.
Vest4		0.15, 0.15, 0.093, 0.16, 0.10
MutPred		0.40		Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);Loss of ubiquitination at K62 (P = 0.063);
MVP		0.95
MPC		0.061
ClinPred		0.15	T
GERP RS		4.8
Varity_R		0.061
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-190660537;