2-189805813-TAAA-TAAAAAA

Variant names:

• chr2-189805813-T-TAAA
• rs3214425
• NM_000534.5:c.418+68_418+70dupAAA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001321049.2(PMS1):​c.486_488dupAAA​(p.Lys163dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000808 in 1,237,216 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: 8.1e-7 (0 hom.)
• Consequence: PMS1 NM_001321049.2 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.609
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001321049.2. Strenght limited to Supporting due to length of the change: 1aa.

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+68_418+70dupAAA		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321049.2		c.486_488dupAAA	p.Lys163dup	disruptive_inframe_insertion	Exon 4 of 4	NP_001307978.1	E9PC40
	PMS1	NM_001321045.2		c.418+68_418+70dupAAA		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+68_418+70dupAAA		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.418+68_418+70dupAAA		intron	N/A	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000424059.1	TSL:1	n.418+68_418+70dupAAA		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 8.08e-7 AC: 1 AN: 1237216 Hom.: 0 Cov.: 31 AF XY: 0.00000163 AC XY: 1 AN XY: 614434

⚠️ 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: 28608

American (AMR) AF: 0.00 AC: 0 AN: 36586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21816

East Asian (EAS) AF: 0.00 AC: 0 AN: 33450

South Asian (SAS) AF: 0.00 AC: 0 AN: 70238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5068

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 945958

Other (OTH) AF: 0.00 AC: 0 AN: 50628

⚠️ 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		-0.61

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3214425; hg19: chr2-190670539;