NM_000251.3:c.67T>C

MSH2 · NP_000242.1:p.(Phe23Leu) · NM_000251.3

GRCh37: chr2:47630397 T>C · GRCh38: chr2:47403258 T>C

Gene: MSH2 Transcript: NM_000251.3

Final call

Benign

BA1

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Phe23Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 c.67T>C (p.Phe23Leu) variant has not been observed in COSMIC somatic cancer records and has been reported in ClinVar predominantly as benign or likely benign, with an aggregate ClinVar classification of Benign.

This variant is present at high frequency in population databases, including gnomAD v4.1 at 410/1600398 alleles with 8 homozygotes and grpmax filtering allele frequency 0.00394201, which exceeds the MSH2 VCEP BA1 threshold.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01; no missense-specific HCI prior value was available to support PP3 or BP4 assessment.

Final determination: BA1 alone meets the stand-alone benign rule; therefore, this variant is classified as 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
PP4	Not assessed	No individual tumor MSI/IHC or phenotype data were identified to support PP4 under the MSH2 VCEP rules.
BP3	N/A	BP3 is designated not applicable in the MSH2 VCEP specification.	cspec
BP7	N/A	NM_000251.3:c.67T>C is a missense variant, not a synonymous or qualifying deep intronic change.	prefetch
BS4	Not assessed	No segregation data or Bayes likelihood ratio were identified.
BS3	Not assessed	No variant-specific calibrated functional assay or qualifying RNA assay demonstrating proficient function was identified.	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
PM5	Not assessed	No evidence was identified in the reviewed sources for a different pathogenic or likely pathogenic missense change at residue Phe23 that would satisfy PM5, and PP3 was not established.
BP2	N/A	BP2 is designated not applicable in the MSH2 VCEP specification.	cspec
PM2	Not met	The variant is not absent or extremely rare in population databases; gnomAD v4.1 shows total AF 0.000256186 with grpmax FAF 0.00394201, well above the PM2_Supporting threshold of <0.00002.	gnomad_v4 gnomad_v2
BP4	Not assessed	For MSH2 missense variants, BP4 requires an HCI prior probability of pathogenicity <0.11; no HCI prior value was identified. The available SpliceAI result is not sufficient for missense BP4 under this VCEP rule.	spliceai
BP6	N/A	BP6 is designated not applicable in the MSH2 VCEP specification.	cspec
PS1	Not assessed	No prior pathogenic or likely pathogenic nucleotide change encoding the same amino acid substitution was identified in the reviewed sources.
PS2	Not assessed	No de novo data were identified.
BS1	Not met	The population frequency exceeds the BS1 range and instead falls into the BA1 range. gnomAD v4.1 grpmax FAF is 0.00394201, which is above the BS1 upper bound of <0.001.	gnomad_v4
PM1	N/A	PM1 is designated not applicable in the MSH2 VCEP 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 designated not applicable in the MSH2 VCEP specification.	cspec clinvar
PP1	Not assessed	No segregation data or Bayes likelihood ratio were identified to support co-segregation.
BP5	Not assessed	No tumor data showing MSS, retained MMR protein expression, or gene-inconsistent IHC loss were identified.
PM6	N/A	PM6 is designated not applicable in the MSH2 VCEP specification.	cspec
BA1	Met	The variant exceeds the MSH2 VCEP BA1 frequency threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.00394201, above the BA1 cutoff of 0.001, with 410/1600398 alleles observed overall and 8 homozygotes. No founder pathogenic exception was identified in the reviewed sources.	gnomad_v4 gnomad_v2 clinvar
PVS1	N/A	NM_000251.3:c.67T>C causes a missense substitution, p.(Phe23Leu), and is not a null variant or qualifying splice variant for PVS1.	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 designated not applicable in the MSH2 VCEP specification.	cspec
PM4	N/A	PM4 is designated not applicable in the MSH2 VCEP specification.	cspec
PS3	Not assessed	No variant-specific calibrated functional assay or qualifying MMR functional flowchart evidence demonstrating an MMR defect was identified for p.Phe23Leu.	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 literature_pass
PP3	Not assessed	For MSH2 missense variants, PP3 requires an HCI prior probability >0.68; no HCI prior value was identified. SpliceAI predicts no significant splice impact, but the splice-based PP3 rule applies to non-canonical splice nucleotides rather than this missense substitution.	spliceai
BS2	Not assessed	No confirmed in trans co-occurrence with a known pathogenic MSH2 variant in an appropriately phenotyped older individual was identified.	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 designated not applicable in the MSH2 VCEP specification.	cspec
PM3	Not assessed	No biallelic observation data or point-based PM3 evidence were identified.
PP2	N/A	PP2 is designated not applicable in the MSH2 VCEP specification.	cspec

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