chr2-189859831-C-T

Variant names:

• chr2-189859831-C-T
• rs256571
• NM_000534.5:c.1857-3912C>T

Variant summary

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

The NM_000534.5(PMS1):​c.1857-3912C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 151,988 control chromosomes in the GnomAD database, including 5,142 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 0.18 (5142 hom., cov: 32)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• Publications: 4 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000534.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	NM_000534.5	MANE Select	c.1857-3912C>T		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.1857-3912C>T		intron	N/A	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.1857-3912C>T		intron	N/A	NP_001307976.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.1857-3912C>T		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000409593.5	TSL:1	c.1211+4703C>T		intron	N/A	ENSP00000387169.1	P54277-4
	PMS1	ENST00000424059.1	TSL:1	n.1740-3912C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28039 AN: 151870 Hom.: 5132 Cov.: 32

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.0867

Gnomad ASJ AF: 0.0841

Gnomad EAS AF: 0.0420

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0939

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0645

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.185 AC: 28090 AN: 151988 Hom.: 5142 Cov.: 32 AF XY: 0.182 AC XY: 13488 AN XY: 74298

African (AFR) AF: 0.479 AC: 19848 AN: 41402

American (AMR) AF: 0.0864 AC: 1320 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0841 AC: 292 AN: 3472

East Asian (EAS) AF: 0.0417 AC: 216 AN: 5182

South Asian (SAS) AF: 0.130 AC: 628 AN: 4820

European-Finnish (FIN) AF: 0.0939 AC: 991 AN: 10550

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0645 AC: 4386 AN: 67976

Other (OTH) AF: 0.164 AC: 347 AN: 2112

Alfa AF: 0.0935 Hom.: 494

Bravo AF: 0.196

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.71
DANN	Benign	0.11
PhyloP100		-0.50
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: rs256571; hg19: chr2-190724557;