chr2-189824998-A-AT

Variant names:

• chr2-189824998-A-AT
• rs5741593
• NM_000534.5:c.582+6821dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_000534.5(PMS1):​c.582+6821dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 152,118 control chromosomes in the GnomAD database, including 847 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.097 (847 hom., cov: 31)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.583
• Publications: 3 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.582+6821dupT		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.582+6818_582+6819insT		intron_variant	Intron 5 of 12	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.0974 AC: 14800 AN: 152000 Hom.: 851 Cov.: 31

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0476

Gnomad EAS AF: 0.0535

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0663

Gnomad OTH AF: 0.0908

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

GnomAD4 genome AF: 0.0973 AC: 14799 AN: 152118 Hom.: 847 Cov.: 31 AF XY: 0.0985 AC XY: 7325 AN XY: 74370

African (AFR) AF: 0.171 AC: 7119 AN: 41514

American (AMR) AF: 0.0546 AC: 835 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 165 AN: 3468

East Asian (EAS) AF: 0.0531 AC: 275 AN: 5182

South Asian (SAS) AF: 0.113 AC: 544 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1120 AN: 10588

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0663 AC: 4501 AN: 67928

Other (OTH) AF: 0.0903 AC: 191 AN: 2114

Alfa AF: 0.0825 Hom.: 80

Bravo AF: 0.0959

Asia WGS AF: 0.0880 AC: 306 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58
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: rs5741593; hg19: chr2-190689724;