rs80356899

Variant names:

• chr17-43092388-C-A
• rs80356899
• NM_007294.4:c.3143G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-43092388-C-A
• chr17-43092388-C-G
• chr17-43092388-C-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_007294.4(BRCA1):​c.3143G>T​(p.Gly1048Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,658 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1048C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:5 B:4
• Conservation: PhyloP100: 0.151
• Publications: 15 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1682125).
• BP6: Variant 17-43092388-C-A is Benign according to our data. Variant chr17-43092388-C-A is described in ClinVar as Benign. ClinVar VariationId is 54777.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.3143G>T	p.Gly1048Val	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.3143G>T	p.Gly1048Val	missense_variant	Exon 10 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251002 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461658 Hom.: 0 Cov.: 39 AF XY: 0.00000275 AC XY: 2 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111918

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Benign

Submissions summary: Uncertain:5 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Jun 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1048V variant (also known as c.3143G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3143. The glycine at codon 1048 is replaced by valine, an amino acid with dissimilar properties. 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. -

Aug 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with valine at codon 1048 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. Multifactorial analyses have reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant, family history and personal and family history of 1.1391, 0.0135 and 1.043, respectively (PMID: 31131967, 31853058). This variant has been identified in 1/251002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 18, 2019

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

IARC 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 = 0.000314 -

not provided Uncertain:1 Benign:1

Aug 04, 2015

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted BRCA1 c.3143G>T at the cDNA level, p.Gly1048Val (G1048V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 3262G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gly1048Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Gly1048Val occurs at a position that is not conserved and is located within the DNA-binding domain and the region of interaction with RAD51 and BASC (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Gly1048Val is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Oct 21, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA1-related cancer predisposition Uncertain:1

Apr 10, 2024

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 glycine with valine at codon 1048 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. A multifactorial analysis has reported co-occurrence and family history likelihood ratios of 1.1391 and 0.0135, respectively (PMID: 31131967). This variant has been identified in 1/251002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Benign:1

Apr 22, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA1 c.3143G>T (p.Gly1048Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251002 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3143G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Cline_2019, Padilla_2019). The following publications have been ascertained in the context of this evaluation (PMID: 15385441, 23893897, 25011685, 31112341, 31294896). ClinVar contains an entry for this variant (Variation ID: 54777). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Benign:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.000098	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.032	N
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L;L;.;.
PhyloP100		0.15
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-4.2	D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.034	D;D;D;D
Sift4G	Benign	0.096	T;T;T;T
Polyphen		0.86	P;.;.;D
Vest4		0.34
MutPred		0.23		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);
MVP		0.50
MPC		0.20
ClinPred		0.14	T
GERP RS		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.18
Mutation Taster		=62/38	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: rs80356899; hg19: chr17-41244405;