rs1145234

Variant names:

• chr2-189867833-T-C
• rs1145234
• NM_000534.5:c.2377T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-189867833-T-C
• chr2-189867833-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000534.5(PMS1):​c.2377T>C​(p.Tyr793His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,579,274 control chromosomes in the GnomAD database, including 70 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y793D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (32 hom.)
• Consequence: PMS1 NM_000534.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.395
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001994431).
• BP6: Variant 2-189867833-T-C is Benign according to our data. Variant chr2-189867833-T-C is described in ClinVar as Benign. ClinVar VariationId is 135049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0131 (1993/152300) while in subpopulation AFR AF = 0.0448 (1862/41558). AF 95% confidence interval is 0.0431. There are 38 homozygotes in GnomAd4. There are 952 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1993 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.2377T>C	p.Tyr793His	missense	Exon 11 of 13	NP_000525.1	P54277-1
	PMS1	NM_001321045.2		c.2377T>C	p.Tyr793His	missense	Exon 12 of 14	NP_001307974.1	P54277-1
	PMS1	NM_001321047.2		c.2377T>C	p.Tyr793His	missense	Exon 11 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.2377T>C	p.Tyr793His	missense	Exon 11 of 13	ENSP00000406490.3	P54277-1
	PMS1	ENST00000409593.5	TSL:1	c.1246T>C	p.Tyr416His	missense	Exon 5 of 7	ENSP00000387169.1	P54277-4
	PMS1	ENST00000424059.1	TSL:1	n.1971+3859T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1980 AN: 152182 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00388 AC: 974 AN: 250934 AF XY: 0.00307

Gnomad AFR exome AF: 0.0464

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000564

Gnomad OTH exome AF: 0.00279

GnomAD4 exome AF: 0.00158 AC: 2258 AN: 1426974 Hom.: 32 Cov.: 26 AF XY: 0.00141 AC XY: 1003 AN XY: 712012

African (AFR) AF: 0.0441 AC: 1443 AN: 32702

American (AMR) AF: 0.00410 AC: 183 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25940

East Asian (EAS) AF: 0.00 AC: 0 AN: 39438

South Asian (SAS) AF: 0.000187 AC: 16 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00578 AC: 33 AN: 5706

European-Non Finnish (NFE) AF: 0.000347 AC: 375 AN: 1080390

Other (OTH) AF: 0.00350 AC: 207 AN: 59222

GnomAD4 genome AF: 0.0131 AC: 1993 AN: 152300 Hom.: 38 Cov.: 32 AF XY: 0.0128 AC XY: 952 AN XY: 74492

African (AFR) AF: 0.0448 AC: 1862 AN: 41558

American (AMR) AF: 0.00392 AC: 60 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68022

Other (OTH) AF: 0.0142 AC: 30 AN: 2112

Alfa AF: 0.00498 Hom.: 28

Bravo AF: 0.0148

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0458 AC: 202

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00449 AC: 545

Asia WGS AF: 0.00260 AC: 9 AN: 3476

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	8.9
DANN	Benign	0.66
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	-0.11	N
PhyloP100		-0.40
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.024
Sift	Benign	0.54	T
Sift4G	Benign	0.54	T
Polyphen		0.0	B
Vest4		0.093
MVP		0.82
MPC		0.075
ClinPred		0.00056	T
GERP RS		-3.4
Varity_R		0.020
gMVP		0.31
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1145234; hg19: chr2-190732559; COSMIC: COSV99066316; COSMIC: COSV99066316;