chr17-43094104-T-C

Variant names:

• chr17-43094104-T-C
• rs55720177
• NM_007294.4:c.1427A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_007294.4(BRCA1):​c.1427A>G​(p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,614,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H476Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:14 O:1
• Conservation: PhyloP100: -0.0500
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01789409).
• BP6: Variant 17-43094104-T-C is Benign according to our data. Variant chr17-43094104-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 54251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.1427A>G	p.His476Arg	missense	Exon 10 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.1427A>G	p.His476Arg	missense	Exon 10 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.1427A>G	p.His476Arg	missense	Exon 10 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.1427A>G	p.His476Arg	missense	Exon 10 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.1427A>G	p.His476Arg	missense	Exon 10 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.1427A>G	p.His476Arg	missense	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000179 AC: 45 AN: 251296 AF XY: 0.000118

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.000231

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: 0.0000664 AC: 97 AN: 1461808 Hom.: 0 Cov.: 34 AF XY: 0.0000509 AC XY: 37 AN XY: 727198

African (AFR) AF: 0.00224 AC: 75 AN: 33478

American (AMR) AF: 0.000179 AC: 8 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: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111984

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000637 AC: 97 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74476

African (AFR) AF: 0.00221 AC: 92 AN: 41578

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000790

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Jul 01, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 07, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The BRCA1 c.1427A>G (p.His476Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide located in the BRCA1, serine-rich domain (IPR025994) (InterPro). 3/5 in silico tools predict a damaging outcome for this variant. A functional study showed no dramatic effect on splicing for this variant (Anczukow_Genes Chromosomes and Cancer_2008). This variant was found in 34/121588 control chromosomes in the control population ExAc and in published studies, predominantly observed in the African subpopulation at a frequency of 0.00298 (31/10404). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has been reported in affected individuals via publications including one paper reporting the variant to co-occur with another deleterious BRCA1 variant, c.943ins10 (Judkins_2005) referenced in BIC, which also reports another individual with a co-occurring deleterious BRCA2 variant, c.5616_5620delAGTAA. This variant is found in two internal specimens co-occuring with pathogenic variants BRCA2 c.2957_2958insG and PMS2 c.2186_2187delTC. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign.

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: BP2, BS1

May 05, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12531920, 25348012, 24728327, 15829246, 16267036, 15235020, 15726418, 22811390, 23192404, 22516946, 26913838, 18273839, 25782689, 16518693, 27527004, 15385441)

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA1 p.His476Arg variant was identified in 3 of 862 proband chromosomes (frequency: 0.003) from individuals or families with breast and or ovarian cancer and triple negative breast cancer cases; variant was not identified in 1362 control chromosomes from healthy individuals (McKean_Cowdin_2005_15726418, Rummel_2013_23192404). The variant was also identified in the following databases: dbSNP (ID: rs55720177) as “With other allele”, ClinVar (1x, as benign by Invitae, 4x as likely benign by Ambry Genetics, GeneDx, Counsyl, Quest Diagnostics, 1x as uncertain significance by BIC 1x ITMI), Clinvitae (4x, as benign and likely benign by ClinVar and Invitae), LOVD 3.0 (7x), UMD-LSDB (6 records, as neutral), BIC (9x). The variant was not identified in Cosmic, MutDB, ARUP Laboratories, and Zhejiang Colon Cancer database. The variant was identified in control databases in 79 of 277056 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 70 of 24036 chromosomes (freq: 0.003), Latino in 9 of 34418 chromosomes (freq: 0.0003), while the variant was not observed in the Other, European Non-Finnish, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant p.His476Arg has been reported to reside with a known deleterious mutation (BRCA1, 943ins10) (Judkins_2005_16267036). The p.His476Arg residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 likely benign.

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

Feb 05, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 30, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome Benign:3

Oct 30, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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.

Mar 02, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Mar 10, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Apr 19, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Nov 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	13
DANN	Benign	0.89
DEOGEN2	Uncertain	0.50	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.050
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.58
Sift	Benign	0.065	T
Sift4G	Benign	0.21	T
Polyphen		0.93	P
Vest4		0.42
MVP		0.81
MPC		0.12
ClinPred		0.027	T
GERP RS		-0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.088
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs55720177; hg19: chr17-41246121;