rs151325573

chr2-189854881-G-Achr2-189854881-G-C

Variant summary

Our verdict is Benign. Variant got -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:3 O:1
• Conservation: PhyloP100: 3.85

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]

LOC105373796 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 135055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PMS1	NM_000534.5	c.1609G>A	p.Glu537Lys	missense_variant	9/13	ENST00000441310.7
LOC105373796	XR_001739151.2	n.319-2024C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PMS1	ENST00000441310.7	c.1609G>A	p.Glu537Lys	missense_variant	9/13	1	NM_000534.5	P1

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

GnomAD3 exomes AF: 0.00219 AC: 546 AN: 249024 Hom.: 3 AF XY: 0.00224 AC XY: 302 AN XY: 135038

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 SAS exome AF: 0.000197

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

Gnomad4 AFR exome AF: 0.000542

Gnomad4 AMR exome AF: 0.00344

Gnomad4 ASJ exome AF: 0.0114

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00266

Gnomad4 OTH exome AF: 0.00224

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

Gnomad4 AFR AF: 0.000747

Gnomad4 AMR AF: 0.00282

Gnomad4 ASJ AF: 0.00952

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.00291

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00294 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

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PMS1 p.Glu361Lys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs151325573) and ClinVar (classified as a VUS by Illumina and Genomic Research Center, Shahid Beheshti University of Medical Sciences for Lynch Syndrome). The variant was identified in control databases in 596 of 280400 chromosomes (3 homozygous) at a frequency of 0.002126 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 101 of 10314 chromosomes (freq: 0.009793), Latino in 103 of 35214 chromosomes (freq: 0.002925), European (non-Finnish) in 354 of 128070 chromosomes (freq: 0.002764), Other in 18 of 7128 chromosomes (freq: 0.002525), African in 13 of 24308 chromosomes (freq: 0.000535), South Asian in 6 of 30404 chromosomes (freq: 0.000197) and European (Finnish) in 1 of 25054 chromosomes (freq: 0.00004); it was not observed in the East Asian population. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Glu361 residue is not conserved in mammals and four out of five computational analyses (SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T;.;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.92	D;.;D;D;D;D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.0070	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationTaster	Benign	0.95	D;D;D;D;D;D
PrimateAI	Benign	0.35	T
Polyphen		0.93, 0.89	.;.;.;P;P;.;.;.;.
Vest4		0.27, 0.27, 0.32, 0.30, 0.34, 0.29
MVP		0.99
MPC		0.16
ClinPred		0.039	T
GERP RS		5.0
Varity_R		0.073
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs151325573; hg19: chr2-190719607; COSMIC: COSV59717585; COSMIC: COSV59717585;