NM_007294.4:c.2597G>A

BRCA1 · NP_009225.1:p.(Arg866His) · NM_007294.4

GRCh37: chr17:41244951 C>T · GRCh38: chr17:43092934 C>T

Gene: BRCA1 Transcript: NM_007294.4

Final call

VUS

BP6 supporting benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Arg866His)

gnomAD AF

1.9831162440769895e-05 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BP6 (Supporting benign): the ENIGMA expert panel classified this variant as Benign.

Overall: VUS - a lone supporting-benign criterion satisfies no ENIGMA benign-combination rule, and the -1 point score lands in the VUS range (-1 to 5).

Final determination: Under ENIGMA BRCA1 v1.2 Table 3, no combination rule is satisfied when the only met criterion is BP6 at supporting-benign strength (Likely Benign needs >=2 supporting-benign or benign strong/moderate paired with another benign criterion; Benign needs BA1 or 2 benign-strong), and with no pathogenic criteria met the variant defaults to 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	Not assessed	Not assessed: insufficient evidence was available to determine whether this variant causes complete loss of BRCA1 function.
PS1	Not assessed	Not assessed: insufficient evidence was available to compare this change with pathogenic variants reported at the same residue.
PS2	Not assessed	Not assessed: insufficient evidence of a confirmed de novo occurrence was available.
PS3	Not assessed	Not assessed: insufficient functional-study evidence of a damaging effect was available.
PS4	Not assessed	Not assessed: insufficient evidence from affected individuals was available.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether the variant falls in a known mutational hotspot.
PM2	Not assessed	Not assessed: population frequency data were insufficient to evaluate rarity.
PM3	Not assessed	Not assessed: insufficient evidence was available to evaluate biallelic inheritance.
PM4	Not assessed	Not assessed: insufficient evidence was available to evaluate a resulting change in protein length.
PM5	Not assessed	Not assessed: insufficient evidence was available to compare this change with pathogenic missense variants at the same codon.
PM6	Not assessed	Not assessed: insufficient evidence of a de novo occurrence without confirmed parentage was available.
PP1	Not assessed	Not assessed: insufficient familial segregation data was available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the gene's missense-variant profile.
PP3	Not assessed	Not assessed: insufficient computational evidence of a damaging effect was available.
PP4	Not assessed	Not assessed: insufficient phenotype-specific data was available.
PP5	Not assessed	Not assessed: insufficient evidence from a reputable pathogenic source was available.
BA1	Not assessed	Not assessed: population frequency data were insufficient to apply the benign frequency threshold.
BS1	Not assessed	Not assessed: population frequency data were insufficient to support a benign frequency.
BS2	Not assessed	Not assessed: insufficient observations of the variant in healthy individuals were available.
BS3	Not assessed	Not assessed: insufficient functional-study evidence of no effect on function was available.
BS4	Not assessed	Not assessed: insufficient evidence of the variant failing to segregate with disease was available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether missense is a disease mechanism in this gene.
BP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant alongside a pathogenic allele in trans.
BP3	Not assessed	Not assessed: insufficient evidence was available to evaluate an in-frame change in a low-complexity region.
BP4	Not assessed	Not assessed: insufficient computational evidence of no damaging effect was available.
BP5	Not assessed	Not assessed: insufficient evidence of an alternate cause of disease in this individual was available.
BP6	Met	Met (supporting benign): the ENIGMA expert panel classified this variant as Benign.	clinvar
BP7	Not assessed	Not assessed: insufficient evidence was available to evaluate the splice impact of this change.

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.