chr17-43094090-G-C

Variant names:

• chr17-43094090-G-C
• rs1397842308
• NM_007294.4:c.1441C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_007294.4(BRCA1):​c.1441C>G​(p.Leu481Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,796 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L481P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:5
• Conservation: PhyloP100: 0.211
• Publications: 10 publications found

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]

BRCA1 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.312326).
• BP6: Variant 17-43094090-G-C is Benign according to our data. Variant chr17-43094090-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 433698.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.1441C>G	p.Leu481Val	missense_variant	Exon 10 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.1441C>G	p.Leu481Val	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461796 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Benign:1

Dec 01, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 481 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least three individuals affected with breast and/or ovarian cancer (PMID: 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA1_001798) and in one hereditary breast and ovarian cancer family that also has an unspecified pathogenic BRCA1 covariant (PMID: 24916970). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PM2(Supporting)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Jan 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L481V variant (also known as c.1441C>G), located in coding exon 9 of the BRCA1 gene, results from a C to G substitution at nucleotide position 1441. The leucine at codon 481 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with a triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res Treat, 2015 Feb;150:71-80). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Aug 03, 2021

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces leucine with valine at codon 481 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least three individuals affected with breast and/or ovarian cancer (PMID: 32772980, 33471991; Leiden Open Variation Database DB-ID BRCA1_001798) and in one hereditary breast and ovarian cancer family that also has an unspecified pathogenic BRCA1 covariant (PMID: 24916970). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: PM2, BP1, BP5 -

Hereditary breast ovarian cancer syndrome Uncertain:1

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 481 of the BRCA1 protein (p.Leu481Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 24916970, 32772980, 34981296). ClinVar contains an entry for this variant (Variation ID: 433698). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Breast and/or ovarian cancer Benign:1

Jun 03, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Leu481Val variant was not identified in the literature but was identified one time in the UMD as an unclassified variant which co-occurred with a known pathogenic mutation in BRCA1 (BRCA1 c.1916T>A (p.Leu639X)), increasing the likelihood that it does not have clinical significance. The p.Leu481 residue is conserved in mammals but not in lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein. Although the p.Leu481Val variant is not located in a known consensus sequence, 3 out of 5 computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a splice donor site at this nucleotide position; however, it should be noted that these computational predictions are not very predictive of pathogenicity. Furthermore, this variant is identified in this individual who has a second pathogenic variant (p.Thr1677IlefsX2), increasing the likelihood that the p.Leu481Val variant does not have clinical significance. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.  -

Familial cancer of breast Benign:1

Feb 09, 2024

MGZ Medical Genetics Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS2_SUP; PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;.;T;T;.
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.
PhyloP100		0.21
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.6	D;D;D;D;.;D;D
REVEL	Pathogenic	0.67
Sift	Benign	0.048	D;D;D;D;.;D;D
Sift4G	Benign	0.13	T;T;T;T;.;T;.
Polyphen		0.99	D;.;.;P;.;.;.
Vest4		0.38
MutPred		0.69		Loss of sheet (P = 0.0011);Loss of sheet (P = 0.0011);.;Loss of sheet (P = 0.0011);.;Loss of sheet (P = 0.0011);.;
MVP		0.95
MPC		0.38
ClinPred		0.15	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.091
gMVP		0.071
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs1397842308; hg19: chr17-41246107; COSMIC: COSV99066401;