NM_000251.3:c.942+3A>G

MSH2 · NP_000242.1:p.? · NM_000251.3

GRCh37: chr2:47641560 A>G · GRCh38: chr2:47414421 A>G

Gene: MSH2 Transcript: NM_000251.3

Final call

PVS1_Strong

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The MSH2 c.942+3A>G (p.?) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with predominantly likely pathogenic submissions, although some submissions classify it as uncertain significance.

This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 3/11,582 alleles (total AF 0.00025902) with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002 and below the BS1 threshold of at least 0.0001.

Published RNA studies reported that this variant disrupts MSH2 donor splicing and generates an exon 5-skipped transcript, supporting a true splice defect despite its non-canonical +3 position.

SpliceAI predicts a low splice effect with a maximum delta score of 0.02, which is below the MSH2 VCEP PP3 threshold of at least 0.2 and within the BP4 threshold of 0.1 or less, but this in silico result is inconsistent with the published RNA evidence.

Final determination: PVS1_Strong alone does not meet an allowed Pathogenic or Likely Pathogenic combination in the applied CSPEC/VCEP final-classification framework; therefore the 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
PVS1	Met	Published RNA studies reported that this non-canonical donor-site variant causes skipping of MSH2 exon 5. Exon 5 corresponds to c.793_942 (150 nucleotides), predicting an in-frame deletion of 50 amino acids, p.Gly265_Gln314del. Under the MSH2 VCEP splice-specific PVS1 framework, confirmed aberrant splicing for a non-canonical splice variant supports PVS1 use; a conservative PVS1_Strong assignment is supported, with human review needed to confirm the extent of loss of full-length transcript and final splice consequence weighting.	cspec PMID:10978353 PMID:16395668
PS3	Not assessed	RNA evidence supports a splice defect, but the retrieved evidence does not provide a calibrated MMR functional assay result or a variant-specific functional assay classification mapped through the MMR functional assay flowchart for PS3.	cspec PMID:10978353 PMID:16395668 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	PS4 is not applicable for this MSH2 VCEP specification.	cspec
PS2	Not assessed	Published literature notes recurrent de novo occurrence of this variant, but the retrieved evidence does not provide case-level MSH2 VCEP de novo point data with confirmed parentage and qualifying tumor evidence needed for PS2 scoring.	cspec PMID:10978353
PS1	Not assessed	No evidence was identified in the retrieved materials showing that a different variant affecting this same non-canonical splice nucleotide has already been established by this VCEP as pathogenic or likely pathogenic with similar or worse splicing prediction.	cspec clinvar vcep_v_c_e_p___p_i_l_o_t___v_a_r_i_a_n_t_s_______m_m_r
PM2	Not met	This variant is present in gnomAD v4.1 with grpmax FAF 0.00004967, which is above the MSH2 VCEP PM2 threshold of less than 0.00002. Although it is absent from gnomAD v2.1, the available gnomAD v4.1 frequency data do not support PM2.	cspec gnomad_v2 gnomad_v4
PM5	N/A	PM5 is a missense-specific criterion and does not apply to this intronic splice-region variant.	cspec
PM6	N/A	PM6 is not applicable for this MSH2 VCEP specification.	cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic MMR variant in a case scored under the MSH2 VCEP PM3 framework.	cspec
PM1	N/A	PM1 is not applicable for this 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
PP3	Not met	SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02. This value is below the MSH2 VCEP PP3 threshold of at least 0.2 for a predicted splice defect, so PP3 is not met.	cspec spliceai
PP4	Not assessed	No case-level microsatellite instability, mismatch repair protein expression, or tumor phenotype data were identified for this individual, so PP4 cannot be scored from the retrieved evidence.	cspec vcep_t_a_b_l_e___f_o_r___c_m_m_r_d___d_i_a_g_n_o_s_i_s
PP1	Not assessed	No segregation dataset with a calculable Bayes likelihood ratio was identified, so PP1 cannot be assessed from the retrieved evidence.	cspec
PP2	N/A	PP2 is not applicable for this MSH2 VCEP specification.	cspec
PP5	N/A	PP5 is not applicable for this MSH2 VCEP specification.	cspec
BA1	Not met	The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BA1 threshold of at least 0.001. The available population frequency does not support BA1.	cspec gnomad_v4
BS1	Not met	The gnomAD v4.1 grpmax FAF for this variant is 0.00004967, which is below the MSH2 VCEP BS1 threshold of at least 0.0001 and less than 0.001. The available population frequency does not support BS1.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in trans with a known pathogenic MSH2 variant in a qualifying individual without clinical manifestations of CMMRD, 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
BS3	Not met	Available RNA studies reported an abnormal splicing effect for this variant, with exon 5 skipping, rather than no mRNA aberration. This evidence argues against BS3.	cspec PMID:10978353 PMID:16395668
BS4	Not assessed	No lack-of-segregation dataset with a Bayes likelihood ratio was identified, so BS4 cannot be assessed from the retrieved evidence.	cspec
BP4	Not met	SpliceAI predicts a low splice effect for this variant, with a maximum delta score of 0.02, which is below the BP4 threshold of 0.1 or less. However, published RNA studies reported exon 5 skipping, so the available evidence does not support using BP4 as a benign criterion for this variant.	cspec spliceai PMID:10978353 PMID:16395668
BP5	Not assessed	No tumor series showing mismatch between tumor findings and the gene harboring this variant were identified, so BP5 cannot be assessed.	cspec
BP7	Not met	This intronic variant is at position c.942+3, which is closer to the splice donor site than the MSH2 VCEP BP7 boundary of +7 or beyond. The variant position does not meet BP7.	cspec
BP6	N/A	BP6 is not applicable for this MSH2 VCEP specification.	cspec
BP3	N/A	BP3 is not applicable for this MSH2 VCEP specification.	cspec
BP2	N/A	BP2 is not applicable for this MSH2 VCEP specification.	cspec
BP1	N/A	BP1 is not applicable for this MSH2 VCEP specification.	cspec
PM4	N/A	PM4 is not applicable for this MSH2 VCEP specification.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.