rs377043696

Variant names:

• chr7-5992000-C-A
• rs377043696
• NM_000535.7:c.961G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-5992000-C-A
• chr7-5992000-C-G
• chr7-5992000-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000535.7(PMS2):​c.961G>T​(p.Val321Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,446,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V321A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PMS2	NM_000535.7	c.961G>T	p.Val321Phe	missense_variant	Exon 9 of 15	ENST00000265849.12	NP_000526.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PMS2	ENST00000265849.12	c.961G>T	p.Val321Phe	missense_variant	Exon 9 of 15	1	NM_000535.7	ENSP00000265849.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1446046 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 720458

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33178

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44712

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26036

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39602

Gnomad4 SAS exome AF: 0.0000116 AC: 1 AN: 85974

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53310

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1097606

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59890

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.;D;.
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.2	L;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.1	D;D;.;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.10	T;D;.;.;.
Sift4G	Benign	0.074	T;T;.;.;.
Polyphen		1.0	D;D;.;.;D
Vest4		0.84
MutPred		0.72		Gain of catalytic residue at P319 (P = 0.1808);.;.;.;.;
MVP		0.86
MPC		0.30
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.58
gMVP		0.78
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377043696; hg19: chr7-6031631;