rs5742938

Variant names:

• chr2-189785232-G-A
• rs5742938
• NM_000534.5:c.-21+639G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-189785232-G-A
• chr2-189785232-G-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.-21+639G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.589 in 152,088 control chromosomes in the GnomAD database, including 29,931 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 0.59 (29931 hom., cov: 33)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 15 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=-0.78).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 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.-21+639G>A		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.-146-114G>A		intron	N/A	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.-21+462G>A		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.-21+639G>A		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.-21+639G>A		intron	N/A	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000921104.1		c.-21+639G>A		intron	N/A	ENSP00000591163.1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89607 AN: 151968 Hom.: 29912 Cov.: 33

Gnomad AFR AF: 0.244

Gnomad AMI AF: 0.837

Gnomad AMR AF: 0.666

Gnomad ASJ AF: 0.739

Gnomad EAS AF: 0.718

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.622

GnomAD4 exome AF: 0.500 AC: 1 AN: 2 Hom.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.589 AC: 89639 AN: 152086 Hom.: 29931 Cov.: 33 AF XY: 0.593 AC XY: 44060 AN XY: 74336

African (AFR) AF: 0.244 AC: 10113 AN: 41468

American (AMR) AF: 0.666 AC: 10173 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.739 AC: 2564 AN: 3468

East Asian (EAS) AF: 0.718 AC: 3709 AN: 5164

South Asian (SAS) AF: 0.706 AC: 3409 AN: 4826

European-Finnish (FIN) AF: 0.700 AC: 7406 AN: 10580

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.735 AC: 49998 AN: 67990

Other (OTH) AF: 0.621 AC: 1313 AN: 2114

Alfa AF: 0.702 Hom.: 20481

Bravo AF: 0.574

Asia WGS AF: 0.668 AC: 2323 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-1.2
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5742938;

hg19: chr2-190649958;