7-5987209-T-C
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1
The NM_000535.7(PMS2):c.1556A>G(p.Tyr519Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000607 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y519Y) has been classified as Benign.
Frequency
Consequence
NM_000535.7 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000131 AC: 20AN: 152166Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251300Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135858
GnomAD4 exome AF: 0.0000534 AC: 78AN: 1461788Hom.: 0 Cov.: 45 AF XY: 0.0000578 AC XY: 42AN XY: 727190
GnomAD4 genome AF: 0.000131 AC: 20AN: 152284Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74448
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
PMS2: PS3:Supporting, BP4 -
- -
This variant is denoted PMS2 c.1556A>G at the cDNA level, p.Tyr519Cys (Y519C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). PMS2 Tyr519Cys has been reported in at least two individuals with suspected Lynch syndrome, one of whom was also found to harbor a pathogenic MSH2 variant (Yurgelun 2015, Lagerstedt-Robinson 2016). It was also identified in an individual with an MSI-high, PMS2-deficient rectal cancer and a truncating PMS2 variant (Nomura 2015). However, the methodology used by Nomura et al. would not be able to distinguish whether Tyr519Cys was identified in PMS2 or its pseudogene, PMS2CL. This variant demonstrated efficient mismatch repair activity in comparison to a repair-deficient control in an in vitro functional assay (Drost 2013). Although this variant was observed in 1000 Genomes, population data in this region of PMS2 are not considered reliable due to high pseudogene homology. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Tyr519Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PMS2 Tyr519Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -
The PMS2 p.Tyr519Cys variant was identified in 10 of 2298 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer or lynch syndrome (Balogh 2006, Lagerstedt-Robinson 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs63750649) as “With Uncertain significance allele", ClinVar (classified as likely benign by Invitae and Ambry Genetics; as uncertain significance by Counsyl, GeneDx and Fulgent Genetics), Clinvitae, MutDB, Mismatch Repair Genes Variant Database, and in Insight Hereditary Tumors Database (3x, effect unknown). The variant was not identified in COGR, Cosmic, or Zhejiang University databases. The variant was identified in control databases in 24 of 277074 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6464 chromosomes (freq: 0.0003), Latino in 11 of 34416 chromosomes (freq: 0.0003), European in 7 of 126622 chromosomes (freq: 0.0001), and South Asian in 4 of 30780 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Tyr519 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, 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. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. A functional in vitro study by Drost (2013) identified MMR activity of the variant in comparison to a negative control suggesting a neutral effect of the variant on protein function. In addition two patients identified with the c.1556A>G variant were also found to have a co-occurring pathogenic variant: MSH2, c.2210+1G>A and PMS2, c.1492del11, suggesting that the c.1556A>G variant may not be of clinical significance (Yurgelun 2015, Nomura 2015). 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 cancer-predisposing syndrome Uncertain:1Benign:2
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
- -
- -
Lynch syndrome 4 Uncertain:2
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
- -
not specified Benign:2
- -
Variant summary: PMS2 c.1556A>G (p.Tyr519Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 1614072 control chromosomes, predominantly at a frequency of 0.00042 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in PMS2 causing Lynch Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1556A>G has been reported in the literature in individuals affected with Lynch syndrome-associated cancers or with suspected Lynch Syndrome (e.g., Yurgelun_2015, Nomura_2015, Lagerstedt-Robinson_2016, Balogh_2006, Okkels_2019, Li_2020), frequently along with PMS2 c.1559C>T (p.A520V; Yurgelun_2015, Nomura_2015, Okkels_2019). However, the variant was found not to segregate with disease in at least one family (e.g., Okkels_2019) and was also classified as a benign/likely benign polymorphism in several publications (e.g., Okkels_2019, Li_2020, Balogh_2006). These reports are not suggestive that the variant is associated with Lynch Syndrome. Additionally, co-occurrences with other pathogenic variants have been reported (MSH2 c.2210+1G>A (Yurgelun_2015); PMS2 c.1492_1502del11 (p.Ser498GlyfsX3; Nomura_2015); MLH1 c.677+3A>G (Okkels_2019); MLH1 c.(1731+1_1732-1)_(*194_?)del, E16-19del (Okkels_2019)), providing supporting evidence for a benign role. Several publications report experimental evidence evaluating an impact on protein function, suggesting the variant does not greatly disrupt normal protein function (e.g., Drost_2013, Nomura_2015, Okkels_2019). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 17016615, 24027009, 27601186, 31391288, 26232782, 31433215, 25980754). ClinVar contains an entry for this variant (Variation ID: 135939). Based on the evidence outlined above, the variant was classified as likely benign. -
Lynch syndrome 4;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
- -
Breast and/or ovarian cancer Benign:1
- -
Hereditary nonpolyposis colorectal neoplasms Benign:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at