17-43095875-T-C

Variant names:

• chr17-43095875-T-C
• rs55680408
• NM_007294.4:c.641A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_007294.4(BRCA1):​c.641A>G​(p.Asp214Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,828 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. D214V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel U:7 B:6
• Conservation: PhyloP100: 0.120
• Publications: 36 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 -8 ACMG points.

• BP6: Variant 17-43095875-T-C is Benign according to our data. Variant chr17-43095875-T-C is described in ClinVar as Benign. ClinVar VariationId is 37689.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.641A>G	p.Asp214Gly	missense_variant	Exon 9 of 23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.641A>G	p.Asp214Gly	missense_variant	Exon 9 of 23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000359 AC: 9 AN: 251038 AF XY: 0.0000295

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: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000623 AC: 91 AN: 1461624 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 727116

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

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

European-Non Finnish (NFE) AF: 0.0000809 AC: 90 AN: 1111886

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000795 Hom.: 0

Bravo AF: 0.0000264

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Benign

Submissions summary: Uncertain:7 Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

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

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA1)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 15, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2017

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

In our experience this variant always co-occurs in cis with c.594-2A>C. The haplotype of c.[594-2A>C; 641A>G] has been shown to be not pathogenic from comprehensive clinical studies (PMID:27008870). We recommend that if c.641A>G is detected in an individual, presence of c.594-2A>C should be verified. If co-occurrence is confirmed, the combination of the two variants is classified as not pathogenic/benign (see SCV000282252.1). If c.641A>G is detected alone, assume clinical significance uncertain in the absence of further evidence. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Dec 08, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D214G variant (also known as c.641A>G), located in coding exon 8 of the BRCA1 gene, results from an A to G substitution at nucleotide position 641. The aspartic acid at codon 214 is replaced by glycine, an amino acid with a few similar properties. This alteration has been detected in conjunction with the BRCA1 alteration c.594-2A>C (IVS9-2A>C) in cis and was predicted to cause a partial exon 10 deletion by an in silico tool; however, a splicing assay showed that a transcript with a partial exon 10 deletion was not detected (Tesoriero AA et al. Hum Mutat. 2005;26:495). This alteration has been detected in an individual diagnosed with breast cancer at age 39 (she also carried the BRCA1 c.594-2A>C and c.4956G>A alterations) whose mother was diagnosed with breast cancer in her late 40s, an individual with bilateral breast cancer, and an individual with an uterine serous carcinoma (Southey MC et al. Br J Cancer. 1999;79:34-9; Borg A et al. Hum Mutat. 2010 Mar;31(3):E1200-40; Pennington KP et al. Cancer. 2013;119:332-8). In one study, large-scale genetic and clinical resources from the ENIGMA, CIMBA and BCAC consortia were used to assess the pathogenicity of the haplotype (c.594-2A>C linked to c.641A>G) carrying this variant. This resulted in the combined odds for causality of 3.23x10-8 for this haplotype, considering case-control, segregation, and breast tumor pathology information. Their data indicate that c.594-2A>C is always in cis with c.641A>G (de la Hoya M et al Hum Mol Genet. 2016; Mar). Of note, this alteration is also designated as and 760A>G in published literature. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analyses. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jan 14, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:1 Benign:2

Mar 03, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26727311, 27495310, 29168416, 28534081, 20104584, 16683254, 20127978, 22811390, 16211554, 26884819, 27008870, 27313609, 26913838, 27515922, 17972171, 26689913, 25348012, 29254167, 28588830, 28695303) -

May 11, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1

Oct 14, 2020

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 214 of the BRCA1 protein (p.Asp214Gly). This variant is present in population databases (rs55680408, gnomAD 0.007%). This variant has been observed in trans (on the opposite chromosome) from at least two different pathogenic variants in BRCA1, in individuals affected with breast cancer (PMID: 25639900, internal data). Considering that biallelic pathogenic variants are expected to be lethal, this evidence indicates that this variant is not a primary cause of disease. This variant is generally observed on the same chromosome as a second BRCA1 variant, c.594-2A>C. Comprehensive clinical validation studies have shown that this BRCA1 haplotype c.[594-2A>C; 641A>G] is not disease causing (PMID: 27008870, 25639900). ClinVar contains an entry for this variant (Variation ID: 37689). 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 80%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 26689913). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. -

not specified Benign:1

Nov 22, 2023

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.641A>G (p.Asp214Gly) 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. However, in vitro functional studies have shown that the variant in isolation leads to an out-of-frame exon 10 skipping (likely resulting in NMD). As c.641A>G is located outside of splice sites, this variant probably disturbs the regulation of exon 10 splicing by destroying splicing enhancer and/or creating splicing silencer elements, a hypothesis supported by an in silico analysis (de la Hoya 2016). On the other hand, the variant very frequently, if not always, is found in complex with c.594-2A>C (located in intron 9), and the two together were shown also to cause an out-of-frame exon 10 skipping. Notably, though the double mutant allele c.[594-2A>C; 641A>G] did not produce detectable levels of full-length transcripts, it produced normal levels of the delta 9,10 transcripts (which is a naturally occurring alternative transcript, with an in-frame deletion of exon 9 and 10), predicted to encode a BRCA1 protein with sufficient tumor suppression function to compensate for the lack of full length transcripts (de la Hoya 2016). Additionally, when testing the protein level effect of this variant (i.e. D214G) in isolation, the variant protein was shown to have proficient HDR activity (Starita_2018). The variant allele was found at a frequency of 5.9e-05 in 1606832control chromosomes (gnomAD database, v4.0 dataset). This frequency is not higher than the estimated maximum expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome (0.001), allowing no conclusion about variant significance. This variant has been found in many HBOC patients, in most cases as a complex allele in cis with c.594-2A>C, however, the complex variant has also been found to co-occur with other pathogenic BRCA mutations (see e.g. Wong-Brown 2016) and other cancer-gene mutations (Lattimore_2021). In addition, a multifactorial analysis considering large scale case-control, segregation and breast cancer pathology information for the complex allele c.[594-2A>C; 641A>G] predicted the complex variant to be not pathogenic (de la Hoya 2016). Eight other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 partly without evidence for independent evaluation, and classified the variant as VUS (n=4) or likely benign (n=3), while the expert panel classified the variant as VUS in isolation, and benign when occurring as a complex with c.594-2A>C. Based on the evidence outlined above, the variant was classified as likely benign. -

BRCA1-related disorder Benign:1

Aug 11, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	9.4
DANN	Benign	0.93
DEOGEN2	Benign	0.086	.;T;.;.;.;.;T;.;.;T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	1.1	L;L;L;L;.;L;.;.;.;.;.;.;.
PhyloP100		0.12
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.073	T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.25	T;T;D;T;T;T;.;T;D;T;.;T;.
Polyphen		0.0010, 0.14, 0.028	.;B;.;.;.;B;.;.;B;.;.;.;.
Vest4		0.27
MVP		0.59
MPC		0.12
ClinPred		0.023	T
GERP RS		-0.43
Varity_R		0.063
gMVP		0.32
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.23		Position offset: -29

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

Other links and lift over

dbSNP: rs55680408; hg19: chr17-41247892;