2-189854881-G-A

Variant names:

• chr2-189854881-G-A
• rs151325573
• NM_000534.5:c.1609G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000534.5(PMS1):​c.1609G>A​(p.Glu537Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00243 in 1,607,300 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 3.85
• Publications: 13 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070312917).
• BP6: Variant 2-189854881-G-A is Benign according to our data. Variant chr2-189854881-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 135055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 313 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.1609G>A	p.Glu537Lys	missense	Exon 9 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.1609G>A	p.Glu537Lys	missense	Exon 10 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.1609G>A	p.Glu537Lys	missense	Exon 9 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.1609G>A	p.Glu537Lys	missense	Exon 9 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000409593.5	TSL:1	c.964G>A	p.Glu322Lys	missense	Exon 4 of 7	ENSP00000387169.1	P54277-4
	PMS1	ENST00000424059.1	TSL:1	n.1492G>A		non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes AF: 0.00207 AC: 314 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00952

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00219 AC: 546 AN: 249024 AF XY: 0.00224

Gnomad AFR exome AF: 0.000513

Gnomad AMR exome AF: 0.00297

Gnomad ASJ exome AF: 0.00988

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00280

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00247 AC: 3591 AN: 1455162 Hom.: 6 Cov.: 29 AF XY: 0.00244 AC XY: 1764 AN XY: 724140

African (AFR) AF: 0.000542 AC: 18 AN: 33210

American (AMR) AF: 0.00344 AC: 153 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.000186 AC: 16 AN: 85798

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53376

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5746

European-Non Finnish (NFE) AF: 0.00266 AC: 2949 AN: 1106724

Other (OTH) AF: 0.00224 AC: 135 AN: 60134

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152138 Hom.: 1 Cov.: 32 AF XY: 0.00194 AC XY: 144 AN XY: 74382

African (AFR) AF: 0.000747 AC: 31 AN: 41516

American (AMR) AF: 0.00282 AC: 43 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 33 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00291 AC: 198 AN: 67982

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00292 Hom.: 2

Bravo AF: 0.00214

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00443 AC: 38

ExAC AF: 0.00188 AC: 228

EpiCase AF: 0.00289

EpiControl AF: 0.00356

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0070	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.8
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.97	N
REVEL	Uncertain	0.43
Sift	Benign	0.050	D
Sift4G	Benign	0.24	T
Polyphen		0.93	P
Vest4		0.27
MVP		0.99
MPC		0.16
ClinPred		0.039	T
GERP RS		5.0
Varity_R		0.073
gMVP		0.28
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs151325573; hg19: chr2-190719607; COSMIC: COSV59717585;