NM_000251.3:c.802dup

MSH2 · NP_000242.1:p.(Ser268PhefsTer16) · NM_000251.3

GRCh37: chr2:47641414 G>GT · GRCh38: chr2:47414275 G>GT

Gene: MSH2 Transcript: NM_000251.3

Final call

PVS1 PM2_Supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Ser268PhefsTer16)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 c.802dup (p.(Ser268PhefsTer16)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic by 1 clinical laboratory.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles).

The duplication causes a frameshift with a premature stop codon at p.(Ser268PhefsTer16), and this truncation is upstream of the MSH2 codon 891 cutoff for PVS1 Very Strong in the InSiGHT specification.

SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, indicating no additional splice effect is predicted beyond the truncating consequence of the duplication.

Final determination: The combination of PVS1 and PM2_Supporting does not satisfy any benign, likely benign, likely pathogenic, or pathogenic rule in the applicable InSiGHT/CSPEC combining framework; therefore this variant is classified as Uncertain Significance.

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
PP4	Not assessed	No tumor microsatellite instability, mismatch repair immunohistochemistry, or phenotype data were identified to show that this variant is associated with a Lynch syndrome-specific clinical presentation under the MSH2 specification.	cspec
BP3	N/A	BP3 is not used in the MSH2 specification.	cspec
BP7	N/A	BP7 applies to synonymous or qualifying intronic variants, whereas this variant is a frameshift duplication.	cspec prefetch
BS4	Not assessed	No segregation data or Bayes likelihood ratio were identified, so lack of co-segregation with disease cannot be evaluated.	cspec
BS3	N/A	The referenced MMR functional assay resources are directed to missense, splice-site, and synonymous variants, and no calibrated benign functional assay data were identified for this frameshift variant.	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 prefetch
PM5	N/A	PM5 applies to missense variants at the same amino acid residue, whereas this variant is a frameshift duplication.	cspec prefetch
BP2	N/A	BP2 is not used in the MSH2 specification.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1, so the observed population frequency is below the MSH2 PM2 threshold of <0.00002 (<1 in 50,000 alleles), supporting PM2 at supporting strength.	cspec gnomad_v4 gnomad_v2
BP4	N/A	BP4 in the MSH2 specification applies to missense variants with a low HCI prior probability or to intronic/synonymous variants with SpliceAI <=0.1; this variant is a frameshift duplication.	cspec spliceai prefetch
BP6	N/A	BP6 is not used in the MSH2 specification.	cspec
PS1	N/A	PS1 applies to the same amino acid change produced by a different nucleotide change or to certain non-canonical splice variants, which is not the mechanism for this frameshift duplication.	cspec prefetch
PS2	Not assessed	No confirmed de novo data were identified, so PS2 cannot be assessed.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, so its filtering allele frequency is below the BS1 threshold of >=0.0001 and BS1 is not met.	cspec gnomad_v4
PM1	N/A	PM1 is not used in the MSH2 specification.	cspec vcep_m_m_r___f_u_n_c_t_i_o_n_a_l___d_o_m_a_i_n_s
PP5	N/A	PP5 is not used in the MSH2 specification.	cspec
PP1	Not assessed	No co-segregation data or Bayes likelihood ratio were identified, so PP1 cannot be assessed.	cspec
BP5	Not assessed	No tumor profile data were identified to show multiple mismatch-repair-inconsistent tumors or MLH1-specific somatic findings that would argue against pathogenicity for an MSH2 variant.	cspec
PM6	N/A	PM6 is not used in the MSH2 specification.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so its filtering allele frequency is below the BA1 threshold of >=0.001 and BA1 is not met.	cspec gnomad_v4
PVS1	Met	This variant is a frameshift duplication predicted to cause p.(Ser268PhefsTer16), introducing a premature termination codon at codon 283. Under the MSH2 InSiGHT specification, nonsense or frameshift variants introducing a premature stop codon at or before codon 891 meet PVS1 at very strong strength, and this truncation is well upstream of that threshold.	cspec pvs1_gene_context pvs1_variant_assessment prefetch vcep_p_v_s_1___d_e_c_i_s_i_o_n_t_r_e_e___m_m_r
PS4	N/A	PS4 is not used in the MSH2 specification.	cspec
PM4	N/A	PM4 is not used in the MSH2 specification.	cspec
PS3	N/A	The referenced MMR functional assay resources are directed to missense, splice-site, and synonymous variants, and no calibrated pathogenic functional assay data were identified for this frameshift variant.	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 prefetch
PP3	N/A	PP3 in the MSH2 specification applies to missense variants with an elevated HCI prior probability or to non-canonical splice variants with SpliceAI >=0.2; this variant is a frameshift duplication.	cspec spliceai prefetch
BS2	Not assessed	No phased in trans co-occurrence with a known pathogenic MSH2 variant and no phenotype data excluding CMMRD were identified, 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
BP1	N/A	BP1 is not used in the MSH2 specification.	cspec
PM3	Not assessed	No phased in trans observations or points-based recessive evidence were identified, so PM3 cannot be assessed.	cspec
PP2	N/A	PP2 is not used in the MSH2 specification.	cspec

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