chr2-189790835-G-C

Variant names:

• chr2-189790835-G-C
• rs3762545
• NM_000534.5:c.-20-955G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000534.5(PMS1):​c.-20-955G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,038 control chromosomes in the GnomAD database, including 4,531 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.24 (4531 hom., cov: 32)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0360
• Publications: 7 publications found

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]

PMS1 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.-20-955G>C		intron_variant	Intron 1 of 12	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.-20-955G>C		intron_variant	Intron 1 of 12	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35763 AN: 151918 Hom.: 4518 Cov.: 32

Gnomad AFR AF: 0.322

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.221

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.235 AC: 35804 AN: 152038 Hom.: 4531 Cov.: 32 AF XY: 0.233 AC XY: 17286 AN XY: 74326

African (AFR) AF: 0.322 AC: 13353 AN: 41460

American (AMR) AF: 0.253 AC: 3859 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 741 AN: 3466

East Asian (EAS) AF: 0.225 AC: 1163 AN: 5166

South Asian (SAS) AF: 0.120 AC: 579 AN: 4822

European-Finnish (FIN) AF: 0.195 AC: 2057 AN: 10558

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13382 AN: 67964

Other (OTH) AF: 0.223 AC: 471 AN: 2114

Alfa AF: 0.229 Hom.: 513

Bravo AF: 0.244

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.34
PhyloP100		0.036
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs3762545; hg19: chr2-190655561;