2-189842308-T-C

Variant names:

• chr2-189842308-T-C
• rs1233258
• NM_000534.5:c.583-1656T>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.583-1656T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 151,736 control chromosomes in the GnomAD database, including 15,487 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 0.41 (15487 hom., cov: 30)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373
• Publications: 20 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.583-1656T>C		intron_variant	Intron 5 of 12	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.583-1656T>C		intron_variant	Intron 5 of 12	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62272 AN: 151618 Hom.: 15465 Cov.: 30

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.313

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.384

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

GnomAD4 genome AF: 0.411 AC: 62336 AN: 151736 Hom.: 15487 Cov.: 30 AF XY: 0.407 AC XY: 30177 AN XY: 74180

African (AFR) AF: 0.712 AC: 29417 AN: 41312

American (AMR) AF: 0.314 AC: 4795 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1293 AN: 3468

East Asian (EAS) AF: 0.411 AC: 2094 AN: 5092

South Asian (SAS) AF: 0.311 AC: 1498 AN: 4812

European-Finnish (FIN) AF: 0.272 AC: 2867 AN: 10538

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19211 AN: 67940

Other (OTH) AF: 0.386 AC: 815 AN: 2110

Alfa AF: 0.339 Hom.: 25000

Bravo AF: 0.426

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.7
DANN	Benign	0.62
PhyloP100		-0.37
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: rs1233258; hg19: chr2-190707034;