rs55720177

chr17-43094104-T-C

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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:13 O:1
• Conservation: PhyloP100: -0.0500

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 54251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43094104-T-C is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.1427A>G	p.His476Arg	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.1427A>G	p.His476Arg	missense_variant	10/23	1	NM_007294.4	P4

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

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251296 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135820

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 SAS 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

Gnomad4 AFR exome AF: 0.00224

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000199

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

Gnomad4 AFR AF: 0.00221

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 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:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	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) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 01, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 07, 2017	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. -

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

Likely benign, criteria provided, single submitter	literature only	Counsyl	Dec 30, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 30, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 10, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 02, 2021	- -

Hereditary breast ovarian cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 19, 2021	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;T;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.84	T;T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.018	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	2.0	M;M;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;.;D;D
REVEL	Uncertain	0.58
Sift	Benign	0.065	T;T;T;T;.;T;T
Sift4G	Benign	0.21	T;T;T;T;.;T;.
Polyphen		0.93	P;.;.;B;.;.;.
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

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

Other links and lift over

dbSNP: rs55720177; hg19: chr17-41246121;