NM_000534.5:c.175G>A

Variant names:

• chr2-189795811-G-A
• rs143265397
• NM_000534.5:c.175G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000534.5(PMS1):​c.175G>A​(p.Glu59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,613,856 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0025 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.07
• Publications: 12 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021964759).
• BP6: Variant 2-189795811-G-A is Benign according to our data. Variant chr2-189795811-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 708165.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 380 AD gene.

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.175G>A	p.Glu59Lys	missense	Exon 3 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.175G>A	p.Glu59Lys	missense	Exon 4 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.175G>A	p.Glu59Lys	missense	Exon 3 of 13	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.175G>A	p.Glu59Lys	missense	Exon 3 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000374826.8	TSL:1	c.175G>A	p.Glu59Lys	missense	Exon 3 of 5	ENSP00000363959.4	Q5XG96
	PMS1	ENST00000424059.1	TSL:1	n.175G>A		non_coding_transcript_exon	Exon 2 of 9

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 152172 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00459

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00275 AC: 691 AN: 251432 AF XY: 0.00280

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00298

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00383 AC: 5595 AN: 1461566 Hom.: 15 Cov.: 30 AF XY: 0.00381 AC XY: 2773 AN XY: 727110

African (AFR) AF: 0.000448 AC: 15 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00241 AC: 63 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00147 AC: 127 AN: 86258

European-Finnish (FIN) AF: 0.00152 AC: 81 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00460 AC: 5113 AN: 1111718

Other (OTH) AF: 0.00242 AC: 146 AN: 60390

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152290 Hom.: 3 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74474

African (AFR) AF: 0.00106 AC: 44 AN: 41554

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4820

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00459 AC: 312 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00352 Hom.: 2

Bravo AF: 0.00244

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00330 AC: 401

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00308

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PMS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.89
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.020
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.015	N
PhyloP100		2.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.19
Sift	Benign	0.51	T
Sift4G	Benign	0.86	T
Polyphen		0.034	B
Vest4		0.27
MVP		0.91
MPC		0.066
ClinPred		0.0055	T
GERP RS		4.8
Varity_R		0.074
gMVP		0.35
Mutation Taster		=98/2	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: rs143265397; hg19: chr2-190660537;