Variant classification summary

NM_001122740.1:c.1163T>A

ESR1 · NP_001116212.1:p.(Met388Lys) · NM_001122740.1

GRCh37: chr6:152332857 T>A · GRCh38: chr6:152011722 T>A

Gene: ESR1 Transcript: NM_001122740.1

Final call

Likely Pathogenic

PM2 moderate PP3 strong

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Met388Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Moderate): the variant is absent from gnomAD v2.1 and v4.1, supporting extreme rarity in population databases.

2

PP3 (Strong): REVEL score 0.977 exceeds the strong pathogenic threshold of >=0.932.

3

Combining one strong and one moderate pathogenic criterion with no benign evidence yields Likely Pathogenic under the generic ACMG/AMP framework.

Final determination: Generic ACMG/AMP 2015 fallback: one strong-strength pathogenic criterion (PP3_Strong) plus one moderate-strength pathogenic criterion (PM2) combine to Likely Pathogenic.

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	N/A	Not applicable: PVS1 covers only null-variant classes (nonsense, frameshift, canonical splice disruption), and this is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether the same amino-acid change has an established pathogenic designation.
PS2	Not assessed	Not assessed: no proband de novo occurrence, parental genotypes, or maternity/paternity confirmation were available.
PS3	Not assessed	Not assessed: no functional assay data for p.Met388Lys were identified in the literature or curated databases.	oncokb
PS4	Not assessed	Not assessed: no variant-specific affected case series or case-control comparison was available.
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether the variant lies in a mutational hotspot or critical functional domain.
PM2	Met	Met (moderate): absent from gnomAD v2.1 and v4.1, supporting extreme rarity in population databases. Flagged for human review: callable coverage at this locus is not yet confirmed.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband observations or phase information with pathogenic comparators in trans or cis were available.
PM4	N/A	Not applicable: PM4 applies to in-frame indels or stop-loss changes, and this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to evaluate whether a pathogenic missense change is established at the same residue.
PM6	Not assessed	Not assessed: no unconfirmed de novo observation with pedigree or parental details was available.
PP1	Not assessed	Not assessed: no segregation data (affected or unaffected relatives, meioses, pedigree structure) were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the gene's rate of benign missense variation.
PP3	Met	Met (strong): REVEL score 0.977 exceeds the strong pathogenic threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical profile was provided.
PP5	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Pathogenic or Likely Pathogenic assertion.	clinvar
BA1	Not met	Not met: no population allele frequency was reported in gnomAD v2.1 or v4.1 to meet the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no frequency exceeding an expected disorder threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no unaffected-carrier, homozygous, or hemizygous observations were available.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional assay data for this variant were available to demonstrate a benign effect.	oncokb
BS4	Not assessed	Not assessed: no non-segregation evidence (unaffected carriers or affected relatives lacking the variant) was available.
BP1	Not assessed	Not assessed: insufficient evidence was available to determine whether missense variants are benign for this gene's disease mechanism.
BP2	Not assessed	Not assessed: no observation of the variant in trans or cis with a pathogenic variant, and no phase information, was available.
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repetitive regions, and this missense substitution does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.977 predicts a pathogenic effect, well above the benign range, so no benign in-silico signal applies.	revel spliceai
BP5	Not assessed	Not assessed: no affected individual or independent pathogenic molecular explanation was provided.
BP6	Not met	Not met: the exact variant is absent from ClinVar, with no expert-panel Benign or Likely Benign assertion.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants with no predicted splice impact, and this missense change alters the protein sequence.	generic_acmg_combination_rules

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.