rs41286290

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4BP6_Very_Strong

The NM_007294.4(BRCA1):​c.1001C>T​(p.Pro334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000706 in 1,613,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

BRCA1
NM_007294.4 missense

Scores

1
7
11

Clinical Significance

Benign reviewed by expert panel B:11

Conservation

PhyloP100: 0.973
Variant links:
Genes affected
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1
In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4
BP4
Computational evidence support a benign effect (MetaRNN=0.26464015).
BP6
Variant 17-43094530-G-A is Benign according to our data. Variant chr17-43094530-G-A is described in ClinVar as [Benign]. Clinvar id is 54099.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094530-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRCA1NM_007294.4 linkc.1001C>T p.Pro334Leu missense_variant 10/23 ENST00000357654.9 NP_009225.1 P38398-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRCA1ENST00000357654.9 linkc.1001C>T p.Pro334Leu missense_variant 10/231 NM_007294.4 ENSP00000350283.3 P38398-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152006
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000199
AC:
5
AN:
251380
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000440
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000753
AC:
110
AN:
1461770
Hom.:
0
Cov.:
34
AF XY:
0.0000811
AC XY:
59
AN XY:
727178
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
0.0000863
Gnomad4 OTH exome
AF:
0.000199
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152006
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74236
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:3
Benign, reviewed by expert panelcurationEvidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)Aug 10, 2015IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000000271 -
Likely benign, criteria provided, single submitterclinical testingCounsylFeb 21, 2017- -
Benign, no assertion criteria providedclinical testingBreast Cancer Information Core (BIC) (BRCA1)May 29, 2002- -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 24, 2017Variant summary: The BRCA1 c.1001C>T (p.Pro334Leu) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect binding of multiple ESE sites. Functional studies show the variant to not affect splicing (Anczukow_2008, Caux-Moncoutier_2009). This variant was found in 2/121404 control chromosomes from ExAC at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005); however, it could still be a rare polymorphism. The variant has been reported in multiple affected individuals via publications and databases, including co-occurrence with other BRCA1 pathogenic variants in other allele (in trans), 2120insA (Judkins_2005), c.66_67delAG (BIC), and an unspecified deleterious variant (Spearman_2008), strongly supporting for benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJul 01, 2020- -
Likely benign, criteria provided, single submitterclinical testingGeneDxMar 09, 2021This variant is associated with the following publications: (PMID: 17924331, 19471317, 21990134, 18824701, 22753008, 18273839, 16267036, 23893897, 25348012, 18703817, 22045683) -
Hereditary cancer-predisposing syndrome Benign:3
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 22, 2019This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Oct 22, 2021- -
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJun 13, 2016- -
BRCA1-related disorder Benign:1
Benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesFeb 27, 2020This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.061
T
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
13
DANN
Benign
0.93
DEOGEN2
Uncertain
0.52
D;.;.;.;T;T;.;.;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.057
N
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.16
D
MetaRNN
Benign
0.26
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.36
T
MutationAssessor
Uncertain
2.5
M;M;.;.;.;.;.;.;.
PrimateAI
Benign
0.24
T
PROVEAN
Pathogenic
-7.4
D;D;D;D;.;D;D;D;D
REVEL
Uncertain
0.45
Sift
Benign
0.040
D;D;D;D;.;D;D;D;D
Sift4G
Benign
0.061
T;T;T;T;.;D;.;T;D
Polyphen
0.58
P;.;.;B;.;.;.;.;.
Vest4
0.37
MVP
0.78
MPC
0.11
ClinPred
0.061
T
GERP RS
1.9
Varity_R
0.085
gMVP
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs41286290; hg19: chr17-41246547; COSMIC: COSV104621708; COSMIC: COSV104621708; API