rs256563

Variant names:

• chr2-189867106-A-G
• rs256563
• NM_000534.5:c.2343-693A>G

Variant summary

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

The NM_000534.5(PMS1):​c.2343-693A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 152,096 control chromosomes in the GnomAD database, including 10,814 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 0.29 (10814 hom., cov: 32)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.283
• Publications: 12 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

ENSG00000300477 (HGNC:):

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 = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS1	NM_000534.5	c.2343-693A>G		intron_variant	Intron 10 of 12	ENST00000441310.7	NP_000525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS1	ENST00000441310.7	c.2343-693A>G		intron_variant	Intron 10 of 12	1	NM_000534.5	ENSP00000406490.3

Frequencies

GnomAD3 genomes AF: 0.289 AC: 43907 AN: 151978 Hom.: 10791 Cov.: 32

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.240

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.185

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.289 AC: 43972 AN: 152096 Hom.: 10814 Cov.: 32 AF XY: 0.287 AC XY: 21322 AN XY: 74374

African (AFR) AF: 0.673 AC: 27884 AN: 41440

American (AMR) AF: 0.217 AC: 3315 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 381 AN: 3468

East Asian (EAS) AF: 0.240 AC: 1242 AN: 5174

South Asian (SAS) AF: 0.173 AC: 836 AN: 4830

European-Finnish (FIN) AF: 0.182 AC: 1931 AN: 10594

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.114 AC: 7754 AN: 67984

Other (OTH) AF: 0.248 AC: 523 AN: 2112

Alfa AF: 0.172 Hom.: 5449

Bravo AF: 0.309

Asia WGS AF: 0.213 AC: 742 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	0.56
DANN	Benign	0.51
PhyloP100		-0.28
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: rs256563; hg19: chr2-190731832;