2-189817925-A-G

Variant names:

• chr2-189817925-A-G
• rs5743042
• NM_000534.5:c.419-92A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000534.5(PMS1):​c.419-92A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 955,896 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (281 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (143 hom.)
• Consequence: PMS1 NM_000534.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.488
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-189817925-A-G is Benign according to our data. Variant chr2-189817925-A-G is described in ClinVar as Benign. ClinVar VariationId is 1182485.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 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.419-92A>G		intron	N/A	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.419-92A>G		intron	N/A	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.419-92A>G		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.419-92A>G		intron	N/A	ENSP00000406490.3	P54277-1
	PMS1	ENST00000424059.1	TSL:1	n.419-92A>G		intron	N/A
	PMS1	ENST00000921104.1		c.419-92A>G		intron	N/A	ENSP00000591163.1

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5023 AN: 152158 Hom.: 281 Cov.: 32

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0249

GnomAD4 exome AF: 0.00373 AC: 2996 AN: 803620 Hom.: 143 AF XY: 0.00309 AC XY: 1301 AN XY: 421454

African (AFR) AF: 0.112 AC: 2363 AN: 21094

American (AMR) AF: 0.00605 AC: 230 AN: 38016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21358

East Asian (EAS) AF: 0.00 AC: 0 AN: 35378

South Asian (SAS) AF: 0.000245 AC: 17 AN: 69520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48768

Middle Eastern (MID) AF: 0.00325 AC: 10 AN: 3080

European-Non Finnish (NFE) AF: 0.000121 AC: 64 AN: 528446

Other (OTH) AF: 0.00822 AC: 312 AN: 37960

GnomAD4 genome AF: 0.0330 AC: 5031 AN: 152276 Hom.: 281 Cov.: 32 AF XY: 0.0311 AC XY: 2317 AN XY: 74470

African (AFR) AF: 0.115 AC: 4767 AN: 41534

American (AMR) AF: 0.0122 AC: 187 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68032

Other (OTH) AF: 0.0246 AC: 52 AN: 2112

Alfa AF: 0.0152 Hom.: 34

Bravo AF: 0.0376

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.4
DANN	Benign	0.68
PhyloP100		-0.49
PromoterAI		0.00090	Neutral
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: rs5743042; hg19: chr2-190682651;