NM_001122740.1:c.1235G>A

ESR1 · NP_001116212.1:p.(Arg412Lys) · NM_001122740.1

GRCh37: chr6:152332929 G>A · GRCh38: chr6:152011794 G>A

Gene: ESR1 Transcript: NM_001122740.1

Final call

VUS

PM1 moderate PM2 moderate

Variant details

Gene

ESR1

Transcript

NM_001122740.1

Protein

NP_001116212.1:p.(Arg412Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

This missense variant (c.1235G>A, p.Arg412Lys) lies within the ESR1 ligand-binding domain (LBD, residues 305–552), a critical functional domain required for estrogen binding and receptor transactivation (PM1).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0% across all populations (PM2).

No functional studies assessing the effect of p.Arg412Lys on ESR1 activity were identified; PS3 is not met.

Computational evidence is inconsistent: REVEL score 0.487 is borderline, BayesDel score 0.300 is indeterminate, and SpliceAI predicts no splicing impact (max delta 0.01); PP3 is not met and BP4 is not met.

The variant is absent from ClinVar, with no pathogenic or benign assertions from any submitter; PS5, PP5, and BP6 are not met.

No published literature reporting this specific variant was identified; PS1, PS2, PS3, PS4, PM6, PP1, and PP4 could not be assessed due to absence of variant-specific clinical or functional data.

With only PM1 (moderate) and PM2 (moderate) met, the variant does not reach the Likely Pathogenic threshold per generic ACMG/AMP 2015 combination rules (PMID:25741868), which require at least 3 moderate criteria or 1 strong criterion for Likely Pathogenic.

This variant is classified as a Variant of Uncertain Significance (VUS) per generic ACMG/AMP 2015 framework.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	N/A	This is a missense variant (c.1235G>A, p.Arg412Lys) and does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No alternate nucleotide change at codon 412 (Arg) with a known pathogenic classification was identified in ClinVar or literature to support PS1.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with maternity and paternity confirmation has been reported for this variant in the literature or public databases.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Arg412Lys on ESR1 protein function were identified.	oncokb
PS4	Not met	The variant is absent from population databases and no case-control study demonstrating statistically significant enrichment in affected individuals versus controls was identified.	gnomad_v2 gnomad_v4 gnomad_canada
PS5	Not met	No pathogenic missense variant at the same codon (Arg412) with a different amino acid change was identified to support PS5.	pm5_candidates
PM1	Met	Residue 412 (Arg) lies within the ESR1 ligand-binding domain (LBD; residues 305–552 of the canonical isoform), a well-established critical functional domain required for estrogen binding and receptor transactivation. The variant is absent from population databases, consistent with absence of benign variation at this position.	gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	Absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes and genomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0% across all populations, well below the PM2 threshold of <0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same residue (Arg412) with a different amino acid change was identified in ClinVar.	pm5_candidates
PM6	Not assessed	No de novo observation without confirmation of paternity and maternity has been reported for this variant.
PP1	Not assessed	No co-segregation data with disease in multiple affected family members are available for this variant.
PP2	Not assessed	HCI prior score is not available for ESR1, precluding assessment of whether the gene has a low rate of benign missense variation.
PP3	Not met	Multiple lines of computational evidence are inconsistent and do not converge to support a deleterious effect: REVEL score 0.487 is below the commonly applied 0.5 pathogenic threshold, BayesDel score 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta score 0.01).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data are available for this variant to assess whether the clinical presentation is highly specific for ESR1-related disease.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar under the queried transcript NM_001122740.1.	clinvar
BA1	Not met	Allele frequency is 0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency is 0% in all population databases, far below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy adults for a fully penetrant dominant disorder.
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect of p.Arg412Lys on ESR1 protein function were identified.
BS4	Not assessed	No segregation data demonstrating lack of association with disease (e.g., unaffected individuals carrying the variant in multiple family members) are available.
BP1	Not assessed	The primary disease mechanism for germline ESR1 variants is not well-established. While literature suggests some support for loss-of-function as a mechanism, there is insufficient evidence that primarily truncating variants cause ESR1-related disease to apply BP1 without a CSPEC/VCEP specification.	pvs1_gene_context
BP2	N/A	ESR1-associated disorders are not known to follow autosomal recessive inheritance; BP2 applies only when a variant is observed in trans with a pathogenic variant for a fully penetrant recessive disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without a known function; this variant is a single-nucleotide substitution.
BP4	Not met	Multiple lines of in silico evidence are inconsistent or indeterminate and do not converge to support a benign effect: REVEL 0.487 is borderline (below the typical 0.5 pathogenic threshold but not clearly benign), BayesDel 0.300 is in an indeterminate range, and SpliceAI predicts no splicing impact (max delta 0.01). Evidence is insufficient to meet BP4.	revel bayesdel spliceai
BP5	Not assessed	No data are available regarding an alternate molecular basis for disease in a patient carrying this variant.
BP6	Not met	No reputable source has recently reported this variant as benign. The variant is absent from ClinVar under the queried transcript NM_001122740.1.	clinvar
BP7	N/A	BP7 applies only to synonymous variants without predicted splice impact; this is a missense variant (p.Arg412Lys).

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