2-189805813-TAAA-TAA

Variant names:

• chr2-189805813-TA-T
• rs3214425
• NM_000534.5:c.418+70delA

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_001321049.2(PMS1):​c.488delA​(p.Lys163SerfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00578 in 1,231,756 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0066 (0 hom.)
• Consequence: PMS1 NM_001321049.2 frameshift
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.609
• Publications: 7 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: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 2-189805813-TA-T is Benign according to our data. Variant chr2-189805813-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3058885.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321049.2. 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.418+70delA		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321049.2		c.488delA	p.Lys163SerfsTer15	frameshift	Exon 4 of 4	NP_001307978.1	E9PC40
	PMS1	NM_001321045.2		c.418+70delA		intron	N/A	NP_001307974.1	P54277-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.418+70delA		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.418+70delA		intron	N/A	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000424059.1	TSL:1	n.418+70delA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 21 AN: 148822 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000201

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000510

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0264 AC: 3518 AN: 133226 AF XY: 0.0279

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.0327

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0197

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0269

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.00655 AC: 7093 AN: 1082844 Hom.: 0 Cov.: 31 AF XY: 0.00710 AC XY: 3798 AN XY: 534708

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

African (AFR) AF: 0.00658 AC: 170 AN: 25854

American (AMR) AF: 0.0207 AC: 646 AN: 31188

Ashkenazi Jewish (ASJ) AF: 0.00911 AC: 167 AN: 18322

East Asian (EAS) AF: 0.00712 AC: 203 AN: 28526

South Asian (SAS) AF: 0.0185 AC: 1009 AN: 54686

European-Finnish (FIN) AF: 0.00707 AC: 272 AN: 38474

Middle Eastern (MID) AF: 0.00528 AC: 24 AN: 4548

European-Non Finnish (NFE) AF: 0.00516 AC: 4318 AN: 837422

Other (OTH) AF: 0.00648 AC: 284 AN: 43824

⚠️ 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: 0.000148 AC: 22 AN: 148912 Hom.: 0 Cov.: 25 AF XY: 0.000179 AC XY: 13 AN XY: 72592

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

African (AFR) AF: 0.000147 AC: 6 AN: 40828

American (AMR) AF: 0.000201 AC: 3 AN: 14908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3430

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4696

European-Finnish (FIN) AF: 0.000510 AC: 5 AN: 9804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000105 AC: 7 AN: 66878

Other (OTH) AF: 0.00 AC: 0 AN: 2044

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000000000340838), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0554 Hom.: 151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PMS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.61
Mutation Taster		=153/47	polymorphism

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: rs3214425; hg19: chr2-190670539; COSMIC: COSV59720199;