2-189805813-TAAA-TA

Variant names:

• chr2-189805813-TAA-T
• rs3214425
• NM_000534.5:c.418+69_418+70delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001321049.2(PMS1):​c.487_488delAA​(p.Lys163ValfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000162 in 1,237,088 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: PMS1 NM_001321049.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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+69_418+70delAA		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321049.2		c.487_488delAA	p.Lys163ValfsTer4	frameshift	Exon 4 of 4	NP_001307978.1	E9PC40
	PMS1	NM_001321045.2		c.418+69_418+70delAA		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+69_418+70delAA		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.418+69_418+70delAA		intron	N/A	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000424059.1	TSL:1	n.418+69_418+70delAA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000751 AC: 1 AN: 133226 AF XY: 0.0000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000174

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000162 AC: 2 AN: 1237088 Hom.: 0 AF XY: 0.00000163 AC XY: 1 AN XY: 614364

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

African (AFR) AF: 0.00 AC: 0 AN: 28606

American (AMR) AF: 0.00 AC: 0 AN: 36562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21812

East Asian (EAS) AF: 0.00 AC: 0 AN: 33448

South Asian (SAS) AF: 0.0000142 AC: 1 AN: 70212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5066

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 945894

Other (OTH) AF: 0.00 AC: 0 AN: 50626

⚠️ 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 Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

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;