Variant classification summary

NM_000535.7:c.321G>A

PMS2 · NP_000526.2:p.(Arg107=) · NM_000535.7

GRCh37: chr7:6043353 C>T · GRCh38: chr7:6003722 C>T

Gene: PMS2 Transcript: NM_000535.7

Final call

Likely Benign

BP7 supporting BP4 supporting PM2 supporting

Variant details

Gene

PMS2

Transcript

NM_000535.7

Protein

NP_000526.2:p.(Arg107=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PMS2 c.321G>A (p.Arg107=) variant has been reported in ClinVar predominantly as likely benign or benign, with a minority submission as uncertain significance.

2

This variant is present at very low frequency in population databases, including gnomAD v4.1 at 11/1598118 alleles (AF 0.0000068831; grpmax FAF 0.00000429) and gnomAD v2.1 at 5/236556 alleles (AF 0.0000211366), which is below the PMS2 PM2_Supporting threshold of 0.00002 in gnomAD v4 and far below the BS1 and BA1 thresholds.

3

In silico evidence supports a benign interpretation because this synonymous variant has no predicted splice effect by SpliceAI, with a maximum delta score of 0.00, supporting BP4 and consistent with BP7.

Final determination: Rule19 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for PMS2 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PS1	N/A	This criterion is not applicable because this variant is a synonymous substitution without predicted splice impact, whereas the PMS2 specification uses PS1 for same-amino-acid missense substitutions or variants affecting the same non-canonical splice nucleotide as an established splice variant.	cspec spliceai
PS2	Not assessed	No confirmed de novo occurrence with the tumor features required by the PMS2 specification was identified, so PS2 cannot be assessed from the available evidence.	cspec
PP4	Not assessed	No colorectal or endometrial tumor MSI results, tumor genome findings, or immunohistochemistry results consistent with PMS2 loss were identified, so PP4 cannot be applied.	cspec
BP3	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BP7	Met	This variant is a synonymous exonic substitution and is outside the PMS2 BP7 splice-region window; SpliceAI also predicts no significant splice impact, which is consistent with BP7 being met.	cspec spliceai
BS2	Not assessed	No evidence was identified that this variant co-occurs in trans with a known pathogenic PMS2 variant in an individual meeting the specification requirements for age and absence of CMMRD features, so BS2 cannot be assessed.	cspec vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
BP4	Met	For this synonymous variant, SpliceAI predicts no splicing impact with a max delta score of 0.00, which is below the PMS2 BP4 threshold of 0.10 and supports BP4.	cspec spliceai
PP1	Not assessed	No segregation data were identified, so the Bayes likelihood ratio required for PP1 could not be calculated.	cspec
PS3	Not assessed	No calibrated functional assay result or RNA study showing a damaging effect for this specific variant was identified, so PS3 cannot be applied.	cspec vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_r vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
BA1	Not met	Population frequency does not meet BA1. The gnomAD v4 grpmax filtering allele frequency is 0.00000429, which is below the BA1 threshold of 0.0028 (0.28%).	gnomad_v4 cspec
PP2	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BP1	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BP6	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
PP5	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BS4	Not assessed	No non-segregation data were identified, so the Bayes likelihood ratio required for BS4 could not be calculated.	cspec
BS3	Not assessed	No variant-specific functional or RNA assay result demonstrating normal function or no mRNA aberration was identified, so BS3 cannot be applied.	cspec vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___s_v_i___d_o_c_u_m_e_n_t_a_t_i_o_n___m_m_r vcep_f_u_n_c_t_i_o_n_a_l___a_s_s_a_y___f_l_o_w_c_h_a_r_t
PS4	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
PM4	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BS1	Not met	Population frequency does not meet BS1. The gnomAD v4 grpmax filtering allele frequency is 0.00000429, which is below the BS1 threshold of 0.00028 (0.028%).	gnomad_v4 cspec
PP3	Not met	Computational evidence does not support PP3. This variant is not missense, and SpliceAI predicts no splice defect with a max delta score of 0.00, which is below the PMS2 PP3 splice threshold of 0.20.	cspec spliceai
PVS1	Not met	PVS1 is not met because this variant is a synonymous substitution rather than a null variant, and SpliceAI predicts no significant splice impact. The generic PVS1 assessment also found that this variant does not fall into a default PVS1 null-variant category.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PM1	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
BP2	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
PM2	Met	Population frequency supports PM2 at supporting strength. In gnomAD v4.1, the allele frequency is 0.0000068831 (11/1598118 alleles) and the grpmax filtering allele frequency is 0.00000429, both below the PMS2 PM2 threshold of 0.00002.	gnomad_v4 cspec
BP5	Not assessed	No tumor data were identified showing microsatellite-stable disease, retained mismatch repair protein expression, or protein loss inconsistent with PMS2, so BP5 cannot be assessed.	cspec
PM6	N/A	This criterion is not used for PMS2 in the applicable specification.	cspec
PM3	Not assessed	No evidence was identified that this variant occurs in trans with another pathogenic PMS2 variant in a context informative for constitutional mismatch repair deficiency scoring, so PM3 cannot be assessed.	cspec vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PM5	N/A	This criterion is not applicable because PM5 is defined for missense changes at an amino acid residue with another pathogenic or likely pathogenic missense change, and this variant is synonymous.	cspec vcep_v_c_e_p___p_i_l_o_t___v_a_r_i_a_n_t_s_______m_m_r

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