chr2-189873586-A-T

Variant names:

• chr2-189873586-A-T
• rs56309301
• NM_000534.5:c.2564A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000534.5(PMS1):​c.2564A>T​(p.Asn855Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,624 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.11
• Publications: 5 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

ENSG00000300477 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41738814).

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.2564A>T	p.Asn855Ile	missense	Exon 12 of 13	NP_000525.1
	PMS1	NM_001321045.2		c.2564A>T	p.Asn855Ile	missense	Exon 13 of 14	NP_001307974.1
	PMS1	NM_001321047.2		c.2564A>T	p.Asn855Ile	missense	Exon 12 of 13	NP_001307976.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS1	ENST00000441310.7	TSL:1 MANE Select	c.2564A>T	p.Asn855Ile	missense	Exon 12 of 13	ENSP00000406490.3
	PMS1	ENST00000409593.5	TSL:1	c.1433A>T	p.Asn478Ile	missense	Exon 6 of 7	ENSP00000387169.1
	PMS1	ENST00000921104.1		c.2672A>T	p.Asn891Ile	missense	Exon 13 of 14	ENSP00000591163.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250960 AF XY: 0.00000737

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449624 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721976

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101016

Other (OTH) AF: 0.00 AC: 0 AN: 59928

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.39	B
Vest4		0.66
MutPred		0.40		Gain of ubiquitination at K851 (P = 0.0561)
MVP		0.99
MPC		0.17
ClinPred		0.74	D
GERP RS		4.8
Varity_R		0.20
gMVP		0.51
Mutation Taster		=82/18	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: rs56309301; hg19: chr2-190738312;